Cleveland Clinic Journal of Medicine

In this issue of the Journal, Dr. Kyle Brizendine reviews the basics of the Ebola virus and its natural history, diagnosis, and management.

Like many of you, I have followed the Ebola story with disquietude. So far, the disease has barely touched our country, with fewer than 10 confirmed cases on US soil, but it has had a big impact on our health care system and our national psyche.

The creation of specialized containment and management units may deplete some hospitals and their communities of intensive care beds. Specially trained caregivers will need to be diverted to staff these units, and the public’s fear may dissuade patients from undergoing elective procedures at hospitals caring for patients with Ebola. All of these pose a financial challenge to the hospitals most capable of dealing with these patients.

We have yet to hear about management guidelines dealing with renal replacement therapy and ventilator support, which may extend life but also pose extra risks to caregivers. Do we understand the disease well enough to know when advanced supportive therapies might be futile? Many lessons were learned from the Liberian patient who died of Ebola in Dallas, but many more clinical questions remain. I had hoped that in our sophisticated ICUs patients treated relatively early with aggressive supportive care would likely survive. We do not yet know if that is true. One death does not make it false, but it does give one pause.

About a half dozen other Ebola patients have survived with treatment here, but they were not African. Does genetic background play a role in disease severity and survival? Were the survivors treated sooner or differently in ways that matter? How much of the end-organ damage from the virus is from direct organ infection that cannot be reversed or prevented by even the best supportive treatment? Does the ability of the virus to suppress the immune system doom patients to opportunistic infections during prolonged supportive therapy? Is the viral-associated immunosuppression enough to prevent some patients from mounting an effective innate (interferon-based) or acquired (viral-specific T-cell or humoral) antiviral response? And is transfusing blood from survivors, presumably conferring passive immunity, actually efficacious?

I was relieved there were no new Ebola cases among the staff caring for Mr. Duncan at his second emergency room visit in Dallas, since at that time he was clearly quite ill, viremic, and contagious. Universal safety precautions must have helped. But how did the other nurses become infected, even though they presumably wore better protection? Hopefully, we will gain further understanding of transmissibility and resistance. We need this knowledge to inform safe and manageable protocols of care, particularly if successful vaccine development is delayed.

In this issue of the Journal, Dr. Kyle Brizendine reviews the basics of the Ebola virus and its natural history, diagnosis, and management.

Like many of you, I have followed the Ebola story with disquietude. So far, the disease has barely touched our country, with fewer than 10 confirmed cases on US soil, but it has had a big impact on our health care system and our national psyche.

The creation of specialized containment and management units may deplete some hospitals and their communities of intensive care beds. Specially trained caregivers will need to be diverted to staff these units, and the public’s fear may dissuade patients from undergoing elective procedures at hospitals caring for patients with Ebola. All of these pose a financial challenge to the hospitals most capable of dealing with these patients.

We have yet to hear about management guidelines dealing with renal replacement therapy and ventilator support, which may extend life but also pose extra risks to caregivers. Do we understand the disease well enough to know when advanced supportive therapies might be futile? Many lessons were learned from the Liberian patient who died of Ebola in Dallas, but many more clinical questions remain. I had hoped that in our sophisticated ICUs patients treated relatively early with aggressive supportive care would likely survive. We do not yet know if that is true. One death does not make it false, but it does give one pause.

About a half dozen other Ebola patients have survived with treatment here, but they were not African. Does genetic background play a role in disease severity and survival? Were the survivors treated sooner or differently in ways that matter? How much of the end-organ damage from the virus is from direct organ infection that cannot be reversed or prevented by even the best supportive treatment? Does the ability of the virus to suppress the immune system doom patients to opportunistic infections during prolonged supportive therapy? Is the viral-associated immunosuppression enough to prevent some patients from mounting an effective innate (interferon-based) or acquired (viral-specific T-cell or humoral) antiviral response? And is transfusing blood from survivors, presumably conferring passive immunity, actually efficacious?

I was relieved there were no new Ebola cases among the staff caring for Mr. Duncan at his second emergency room visit in Dallas, since at that time he was clearly quite ill, viremic, and contagious. Universal safety precautions must have helped. But how did the other nurses become infected, even though they presumably wore better protection? Hopefully, we will gain further understanding of transmissibility and resistance. We need this knowledge to inform safe and manageable protocols of care, particularly if successful vaccine development is delayed.

In this issue of the Journal, Dr. Kyle Brizendine reviews the basics of the Ebola virus and its natural history, diagnosis, and management.

Like many of you, I have followed the Ebola story with disquietude. So far, the disease has barely touched our country, with fewer than 10 confirmed cases on US soil, but it has had a big impact on our health care system and our national psyche.

The creation of specialized containment and management units may deplete some hospitals and their communities of intensive care beds. Specially trained caregivers will need to be diverted to staff these units, and the public’s fear may dissuade patients from undergoing elective procedures at hospitals caring for patients with Ebola. All of these pose a financial challenge to the hospitals most capable of dealing with these patients.

We have yet to hear about management guidelines dealing with renal replacement therapy and ventilator support, which may extend life but also pose extra risks to caregivers. Do we understand the disease well enough to know when advanced supportive therapies might be futile? Many lessons were learned from the Liberian patient who died of Ebola in Dallas, but many more clinical questions remain. I had hoped that in our sophisticated ICUs patients treated relatively early with aggressive supportive care would likely survive. We do not yet know if that is true. One death does not make it false, but it does give one pause.

About a half dozen other Ebola patients have survived with treatment here, but they were not African. Does genetic background play a role in disease severity and survival? Were the survivors treated sooner or differently in ways that matter? How much of the end-organ damage from the virus is from direct organ infection that cannot be reversed or prevented by even the best supportive treatment? Does the ability of the virus to suppress the immune system doom patients to opportunistic infections during prolonged supportive therapy? Is the viral-associated immunosuppression enough to prevent some patients from mounting an effective innate (interferon-based) or acquired (viral-specific T-cell or humoral) antiviral response? And is transfusing blood from survivors, presumably conferring passive immunity, actually efficacious?

I was relieved there were no new Ebola cases among the staff caring for Mr. Duncan at his second emergency room visit in Dallas, since at that time he was clearly quite ill, viremic, and contagious. Universal safety precautions must have helped. But how did the other nurses become infected, even though they presumably wore better protection? Hopefully, we will gain further understanding of transmissibility and resistance. We need this knowledge to inform safe and manageable protocols of care, particularly if successful vaccine development is delayed.

A 50-year-old man who returned from a business trip to Nigeria 24 days ago presents with complaints of the sudden onset of fever, diarrhea, myalgia, and headache. He reports 10 bowel movements per day and has seen bloody stools.

During his trip he flew in to Murtala Muhammed International Airport in Lagos, ate meals only in his hotel, and attended meetings in Lagos central business district. He had no exposure to animals, mosquitoes, ticks, or sick people, and no sexual activity. After returning home, he felt well for the first 3 weeks.

The patient has a history of hypertension. He does not smoke, drink alcohol, or use injection drugs. He is married, works with commercial banks and financial institutions, and lives in Cleveland, OH.

On physical examination his temperature is 100.0˚F (37.8˚C), pulse 98, respirations 15, blood pressure 105/70 mm Hg, and weight 78 kg (172 lb). He appears comfortable but is a little diaphoretic. His abdomen is tender to palpation in the epigastrium and slightly to the right; he has no signs of peritonitis. His skin is without rash, bleeding, or bruising. The remainder of the examination is normal.

His white blood cell count is 17 × 10⁹/L, hemoglobin 15 g/dL, hematocrit 41%, and platelet count 172 × 10⁹/L. His sodium level is 126 mmol/L, potassium 3.8 mmol/L, chloride 95 mmol/L, carbon dioxide 20 mmol/L, blood urea nitrogen 11 mg/dL, creatinine 0.7 mg/dL, and glucose 130 mg/dL. His aminotransferase and alkaline phosphatase levels are normal.

Could this patient have Ebola virus disease?

With Ebola virus disease on the rise in West Africa, physicians who encounter patients like this one need to include it in the differential diagnosis. Because the disease is new, many questions are raised for which we as yet have no answers. Here, I will review what we know and do not know in an effort to remove some of the fear and uncertainty.

A NEW DISEASE

Ebola virus disease is a severe hemorrhagic fever caused by negative-sense single-stranded RNA viruses classified by the International Committee on Taxonomy of Viruses as belonging to the genus Ebolavirus in the family Filoviridae. Filoviruses get their name from the Latin filum, or thread-like structure.

The family Filoviridae was discovered in 1967 after inadvertent importation of infected monkeys from Uganda into Yugoslavia and Marburg, Germany. Outbreaks of severe illness occurred in workers at a vaccine plant who came into direct contact with the animals by killing them, removing their kidneys, or preparing primary cell cultures for polio vaccine production.

Ebola virus was discovered in 1976 by Peter Piot, who was working at the Institute of Tropical Medicine in Antwerp, Belgium. The blood of a Belgian woman who had been working in what is now the Democratic Republic of the Congo (formerly Zaire) had been sent to the institute; she and Mabalo Lokela, a school headmaster and the first recorded victim of Ebola virus, had been working near Yambuku, about 96 km from the Ebola River.

Before the 2014 outbreak, all known outbreaks had caused fewer than 2,400 cases across a dozen African countries over 3 decades.

Five species of Ebola virus

The genus Ebolavirus contains five species, each associated with a consistent case-fatality rate and a more or less well-identified endemic area.¹

Zaire ebolavirus was recognized in 1976; it has caused multiple outbreaks, with high case-fatality rates.

Sudan ebolavirus was seen first in the 1970s; it has a 50% case-fatality rate.

Tai Forest ebolavirus has been found in only one person, an ethologist working with deceased chimpanzees.

Bundibugyo ebolavirus emerged in 2007 and has a 30% case-fatality rate.

Reston ebolavirus is maintained in an animal reservoir in the Philippines and is not found in Africa. It caused an outbreak of lethal infection in macaques imported into the United States in 1989. There is evidence that Reston ebolavirus can cause asymptomatic infection in humans. None of the caretakers of the macaques became ill, nor did farmers working with infected pigs, although both groups seroconverted.

A reservoir in bats?

A reservoir in nonhuman primates was initially suspected. However, studies subsequently showed that monkeys are susceptible to rapidly lethal filoviral disease, precluding any role as a host for persistent viral infection. It is likely that Ebola virus is maintained in small animals that serve as a source of infection for both humans and wild primates. A prominent suspect is fruit bats, which are consumed in soup in West Africa.

Transmission is person-to-person or nosocomial

Ebola virus is transmitted by direct contact with body fluids such as blood, urine, sweat, vomitus, semen, and breast milk. Filoviruses can initiate infection via ingestion, inhalation (although probably not Ebola), or passage through breaks in the skin. Droplet inoculation into the mouth or eyes has been shown to result from inadvertent transfer of virus from contaminated hands. Patients transmit the virus while febrile and through later stages of disease, as well as postmortem through contact with the body during funeral preparations. The virus has been isolated in semen for as many as 61 days after illness onset.

One primary human case generates only one to three secondary cases on average, but the case-fatality rate is high

Ebola virus can also be spread nosocomially. In 1976, a 44-year-old teacher sought care for fever at the Yambuku Mission Hospital. He was given parenteral chloroquine as empiric treatment for presumed malaria, which was routine for all febrile patients. However, he had unrecognized Ebola virus infection. Moreover, syringes were rinsed in the same pan of water and reused, which spread the infection to nearly 100 people, all of whom developed fulminant Ebola virus disease and died. Infection then spread to family caregivers, the hospital staff, and those who prepared the bodies for burial.

Nosocomial transmission was also responsible for an outbreak of Lake Victoria Marburg virus in Uige Province in northern Angola in 2005, with 374 putative cases and 329 deaths. When teams from Médecins Sans Frontières started setting up the Marburg ward, there were five patients with hemorrhagic fever in a makeshift isolation room in the hospital, together with corpses that the hospital staff had been too afraid to remove. Healers found in many rural African communities were administering injections in homes or in makeshift clinics with reused needles or syringes.²

There is no evidence that filoviruses are carried by mosquitoes or other biting arthropods. Also, the risk of transmission via fomites appears to be low when currently recommended infection-control guidelines for the viral hemorrhagic fevers are followed.³ One primary human case generates only one to three secondary cases on average.

EBOLA IS AN IMMUNODEFICIENCY VIRUS

The main targets of infection are endothelial cells, mononuclear phagocytes, and hepatocytes. Ebola virus replicates at an unusually high rate. Macrophages infected with Zaire ebolavirus produce tumor necrosis factor alpha, interleukin (IL) 1 beta, IL-6, macrophage chemotactic protein 1, and nitric oxide. Virus-infected macrophages synthesize cell-surface tissue factor, triggering the extrinsic coagulation pathway.

Ebola is an immunodeficiency virus. Dendritic cells, which initiate adaptive immune responses, are a major site of filoviral replication. Infected cells cannot present antigens to naïve lymphocytes. Patients who die of Ebola virus disease do not develop antibodies to the virus. Lymphocytes remain uninfected, but undergo “bystander” apoptosis induced by inflammatory mediators.

CLINICAL MANIFESTATIONS

The incubation period is generally 5 to 7 days (range 2 to 28 days), during which the patient is not infectious. Symptoms begin abruptly, with fever, chills, general malaise, weakness, severe headache, and myalgia. By the time of case detection in West Africa, most patients also had nausea, vomiting, diarrhea, and abdominal pain. Once symptoms arise, patients have high levels of the virus in their blood and fluids and are infectious. Hemorrhagic symptoms have apparently been uncommon in West Africa, occurring in 1.0% to 5.7%, but “unexplained bleeding” has been documented in 18% of cases.⁴ Among those in whom the disease enters its hemorrhagic terminal phase, there is characteristic internal and subcutaneous bleeding, vomiting of blood, and subconjunctival hemorrhage.⁴

Laboratory findings include lymphocytopenia (often with counts as low as 1.0 × 10⁹/L), thrombocytopenia (with counts in the range of 50 to 100 × 10⁹/L), elevated aminotransferase levels (including aspartate aminotransferase levels 7 to 12 times higher than alanine aminotransferase in fatal cases), low total protein (due to capillary leak), and disseminated intravascular coagulation. Those who survive begin to improve in the second week, during which viremia resolves in association with the appearance of virus-specific antibodies.⁴

DIAGNOSIS

In symptomatic patients, Ebola virus infection is diagnosed by detection in blood or body fluids of viral antigens by enzyme-linked immunosorbent assay, or RNA sequences by reverse transcriptase polymerase chain reaction. The diagnosis is confirmed with cell culture (in a BSL-4 containment laboratory) showing characteristic viral particles by electron microscopy.

CARING FOR PATIENTS

The most detailed descriptions of the care of patients with Ebola virus disease have come from Dr. Bruce Ribner, of Emory University Hospital, in an October 2014 report of his experience caring for Ebola-infected patients at Emory University Hospital in Atlanta, GA.⁵ He described fluid losses of 5 to 10 L/day, profound hyponatremia, hypokalemia, and hypocalcemia, which were associated with cardiac arrhythmias and the need for intravenous and oral electrolyte repletion and hemodialysis. Intensive one-to-one nursing was critical, as was the coordination of many medical subspecialties. The Emory team arranged point-of-care testing near the unit and generally kept laboratory testing to a minimum. The team was surprised to learn that commercial carriers refused to transport specimens even when they were licensed for category A agents. Difficulties with the local water authority and waste disposal contractor required the hospital to dedicate an autoclave to process all materials used in clinical care.

TREATMENT: SUPPORTIVE AND EXPERIMENTAL

Treatment is supportive to maintain circulatory function and blood pressure and to correct coagulopathy. However, a variety of vaccines, antibodies, small-molecule agents, and antiviral agents are undergoing testing, mostly in animals at this point.

Vaccines. A therapeutic vaccine that worked only slightly was a live-attenuated recombinant vesicular stomatitis virus expressing Ebola virus transmembrane glycoproteins, which was tested in mice, guinea pigs, and rhesus macaques who had been exposed to Ebola virus.⁶

Incubation is about 5–7 days, during which the patient is not infectious

A preventive vaccine worked better. Stanley et al⁷ evaluated a replication-defective chimpanzee adenovirus 3-vectored vaccine that also contained Ebola virus glycoprotein. They gave macaques a single injection of this vaccine, and then 5 weeks later gave them a lethal dose of Ebola virus. All the vaccinated animals survived the infection, and half (2 of 4) survived when challenged 10 months later. With a prime-boost strategy (modified vaccinia virus Ankara, a poxvirus), all survived when challenged 10 months later.

KZ52, a neutralizing antibody, did not work. Oswald et al⁸ gave a human IgG monoclonal antibody against Zaire Ebola virus, designated KZ52, to four rhesus macaques, challenged them with the virus 24 hours later, and administered a second shot of KZ52 on day 4. All of them died.

ZMAb is a combination of three murine monoclonal antibodies, designated 1H3, 2G4, and 4G7. Ad-IFN is a human adenovirus, serotype 5, that expresses human interferon alpha. Qui et al⁹ gave ZMAb and Ad-IFN to macaques in several experiments. In experiment 1, eight macaques were infected and then were given ZMAb and Ad-IFN 3 days later, and ZMAb again on days 6 and 9. Seven of the eight survived. In a second experiment, Ad-IFN was given first, when the viral load was still less than the limit of detection of known assays, and then ZMAb was given upon detection of viremia and fever. Two of four macaques survived. Control animals had undetectable levels of IgG, whereas Ebola virus GP–specific IgG levels were detected in all survivors. IFN-gamma ELISpots showed high EBOV-GP–specific T-cell response in all survivors.

ZMapp is another cocktail of monoclonal antibodies, containing two from ZMab (2G4 and 4G7), plus a third, c13C6. In experiments in rhesus macaques, three groups of six animals each received three doses of ZMapp at varying times after being infected with Ebola virus: at 3, 6, and 9 days; at 4, 7, and 10 days, and at 5, 8, and 11 days. All 18 macaques treated with ZMapp survived. Thus, Zmapp extended the treatment window to 5 days postexposure.¹⁰ One of the American health care workers who contracted Ebola virus in Liberia received this medication.

HSPA5-PMO. Endoplasmic reticulum chaperone heat shock 70 kDa protein 5 (HSPA5) is instrumental in the maturation of envelope proteins in hepatitis C and influenza A virus. It plays a role in viral entry for coxsackievirus A9 and dengue virus serotype 2, and it may be involved in Ebola viral budding. Phosphorodiamidate morpholino oligomers (PMOs) are a class of antisense DNA nucleotide analogs.

Reid et al¹¹ reported that mice treated with HSPA5–PMO were completely protected from lethal Ebola challenge. Therefore, HSPA5 appears to be a promising target for the development of antifilovirus countermeasures.

Favipiravir, an antiviral agent also known as T-705, is a pyrazinecarboxamide derivative. Invented in 2002 by Toyama Chemicals as an inhibitor of influenza virus replication, it acts as a nucleotide analog, selectively inhibiting the viral RNA-dependent RNA polymerase, or causes lethal mutagenesis upon incorporation into the virus RNA. Favipiravir suppresses Ebola virus replication by 4 log₁₀ units in cell culture.¹²

Mice were challenged with intranasal inoculation of 1,000 focus-forming units of Ebola virus diluted in phosphate-buffered saline. Until the first day of treatment (postinfection day 6), all mice in the T-705 group lost weight similarly to control mice, developed viremia, and showed elevated serum levels of aspartate aminotransferase and alanine aminotransferase. Within 4 days of T-705 treatment (post-infection day 10), the animals had cleared the virus from blood. Surviving mice developed Ebola virus-specific antibodies and CD8+ T cells specific for the viral nucleoprotein.¹²

The authors hypothesized that suppression of virus replication by T-705 allowed the host to mount a virus-specific adaptive immune response, and concluded that T-705 was 100% effective in the treatment of Zaire Ebola virus infection up to postinfection day 6 but was hardly beneficial at the terminal stage of disease.¹² Of note, favipiravir is undergoing phase 2 and phase 3 trials as an anti-influenza agent in Japan.

THE CURRENT OUTBREAK

The current outbreak is with Zaire ebolavirus. It seems to have started in a 2-year-old child who died in Meliandou in Guéckédou Prefecture, Guinea, on December 6, 2013. On March 21, 2014, the Guinea Ministry of Health reported the outbreak of an illness characterized by fever, severe diarrhea, vomiting, and a high case-fatality rate (59%) in 49 persons. On May 25, 2014, Kenema Government Hospital confirmed the first case of Ebola virus disease in Sierra Leone, probably brought there by a traditional healer who had treated Ebola patients from Guinea. Tracing led to 13 additional cases—all women who attended the burial.¹³

The Center for Systems Biology at Harvard University and the Broad Institute of Massachusetts Institute of Technology generated 99 Ebola virus genome sequences from 78 patients with confirmed disease, representing more than 70% of the patients diagnosed with the disease in Sierra Leone from May to mid-June 2014. They found genetic similarity across the sequenced 2014 samples, suggesting a single transmission from the natural reservoir, followed by human-to-human transmission during the outbreak. Continued human-reservoir exposure is unlikely to have contributed to the growth of this epidemic.¹⁴

As of October 14, 2014, there were 8,914 suspected and confirmed cases of Ebola virus infection, and 4,477 deaths.¹⁵

Favipiravir is undergoing phase 2 and phase 3 trials as an anti-influenza agent in Japan

But how did Zaire Ebola virus make the 2,000-mile trek from Central Africa to Guinea in West Africa? There are two possibilities: it has always been present in the region but we just never noticed, or it was recently introduced. Bayesian phylogenetic analyses and sequence divergence studies suggest the virus has been present in bat populations in Guinea without previously infecting humans.

Why Guinea and why Guéckédou? Guinea is one of the poorest countries in the world, ranking 178th of 187 countries on the Human Development Index of the United Nations Development Programme, just behind Liberia (174th) and Sierra Leone (177th). In Guinea, the life expectancy is 56 years and the gross national income per capita is $440. The region has been systematically plundered and the forest decimated by clear-cut logging, leaving the Guinea Forest Region largely deforested, resulting in increased contact between humans and the small animals that serve as the source of infection.¹

LIMITED CAPACITY, EVEN IN THE UNITED STATES

A few hospitals in the United States have dedicated units to handle serious infectious diseases such as Ebola: Emory University Hospital; Nebraska Medicine in Omaha; Providence St. Patrick Hospital in Missoula, MT; and the National Institutes of Health in Bethesda, MD. However, in total they have only 19 beds.

QUESTIONS, ANSWERS—AND MORE QUESTIONS

(The following is from a question-and-answer discussion that followed Dr. Brizendine’s Grand Rounds presentation.)

Q: Are there any differences between survivors and those who die of the disease? A: We do not know. Patient survival depends on early recognition and supportive care. There are disparities in the care of patients. Schieffelin et al¹⁶ analyzed the characteristics of patients who died or who survived in Sierra Leone and found that the mortality rate was higher in older patients and those with a higher viral load on presentation.

Q: Does the virus block production or release of interferon early in infection? A: Yes, it has been shown¹⁷ that Ebola virus protein VP24 inhibits signaling downstream of both interferon alpha/beta and interferon gamma by indirectly impairing the transport of a transcription factor termed STAT1. VP24 is also able to bind STAT1 directly. The resulting suppression of host interferon very early on in the incubation phase is key to the virulence of the virus.

Mutations are occurring but are not changing the characteristics of the Ebola virus

Q: Does infection with one of the viral species confer immunity from other species? A: No, there is no cross-immunity.

Q: How soon do patients test positive? A: About 5 days after exposure, when they develop a fever. At this time patients are highly viremic, which PCR can detect.

Q: Before the virus is detectable in the blood, where is it? A: The liver, endothelial cells, antigen-presenting cells, and adrenal glands.

Q: Do we really need to quarantine ill patients and health care workers returning from Africa, per CDC recommendations? A: We don’t know everything, and some people do make bad decisions, such as traveling while symptomatic. I support a period of observation, although confinement is not reasonable, as it may pose a disincentive to cooperation.

Q: What is the role of giving plasma from survivors? A: Dr. Kent Brantly (see American citizens infected with Ebola) received the blood of a 14-year-old who survived. We don’t know. It is not proved. It did not result in improvement in animal models.

Q: Is the bleeding caused by a mechanism similar to that in enterohemorrhagic Escherichia coli infection? A: No. That is a bacterial toxin, whereas this is more like disseminated intravascular coagulation, with an intrinsic pathway anticoagulation cascade.

Q: How long does the virus remain viable outside the body? A: In one study,¹⁸ Ebola virus could not be recovered from experimentally contaminated surfaces (plastic, metal or glass) at room temperature. In another in which it was dried onto a surface,¹⁹ Ebola virus survived in the dark for several hours between 20 and 25°C. When dried in tissue culture media onto glass and stored at 4°C, it has survived for over 50 days.

Q: How long does the virus remain in breast milk? A: We know it has been detected 15 days after disease onset and think possibly as late as 28 days from symptom onset.³

Q: How are people actually infected? A: I believe people get the virus on their hands and then touch their face, eyes, or mouth. If you are wearing personal protective equipment, it must occur while doffing the equipment.

Q: Could we increase the sensitivity of the test so that we could detect the virus before the onset of symptoms? A: In theory it may be possible. The virus is somewhere in the body during the incubation period. Perhaps we could sample the right compartment in an enriched mononuclear cell line.

Q: When can patients who recover resume their normal activities? A: After their viral load returns to 0, I would still advise abstaining from unprotected sex and from breastfeeding for a few months. but as for other activities, no special precautions are needed.

Q: Does the virus appear to be mutating at a high rate? A: Looking back to 2004, mutations are occurring, but there is no sign that any of these mutations has contributed to the size of the outbreak by changing the characteristics of the Ebola virus. Can it become aerosolized? It has been suggested that the virus that caused the outbreak separated from those that caused past Ebola outbreaks but does not seem to be affecting the spread or efficacy of experimental drugs and vaccines. So, even though it is an RNA virus and mutations are occurring, no serious changes have emerged.¹⁴

BACK TO OUR PATIENT

The differential diagnosis for the patient described at the beginning of this paper includes travelers’ diarrhea, malaria, typhoid fever, yellow fever, meningococcal disease … and Ebola virus disease, although this is much less likely in view of the epidemiology and incubation period of this disease. When his stool was tested by enzyme immunoassay and culture, it was found to be positive for Campylobacter. He recovered with oral rehydration.

A 50-year-old man who returned from a business trip to Nigeria 24 days ago presents with complaints of the sudden onset of fever, diarrhea, myalgia, and headache. He reports 10 bowel movements per day and has seen bloody stools.

During his trip he flew in to Murtala Muhammed International Airport in Lagos, ate meals only in his hotel, and attended meetings in Lagos central business district. He had no exposure to animals, mosquitoes, ticks, or sick people, and no sexual activity. After returning home, he felt well for the first 3 weeks.

The patient has a history of hypertension. He does not smoke, drink alcohol, or use injection drugs. He is married, works with commercial banks and financial institutions, and lives in Cleveland, OH.

On physical examination his temperature is 100.0˚F (37.8˚C), pulse 98, respirations 15, blood pressure 105/70 mm Hg, and weight 78 kg (172 lb). He appears comfortable but is a little diaphoretic. His abdomen is tender to palpation in the epigastrium and slightly to the right; he has no signs of peritonitis. His skin is without rash, bleeding, or bruising. The remainder of the examination is normal.

His white blood cell count is 17 × 10⁹/L, hemoglobin 15 g/dL, hematocrit 41%, and platelet count 172 × 10⁹/L. His sodium level is 126 mmol/L, potassium 3.8 mmol/L, chloride 95 mmol/L, carbon dioxide 20 mmol/L, blood urea nitrogen 11 mg/dL, creatinine 0.7 mg/dL, and glucose 130 mg/dL. His aminotransferase and alkaline phosphatase levels are normal.

Could this patient have Ebola virus disease?

With Ebola virus disease on the rise in West Africa, physicians who encounter patients like this one need to include it in the differential diagnosis. Because the disease is new, many questions are raised for which we as yet have no answers. Here, I will review what we know and do not know in an effort to remove some of the fear and uncertainty.

A NEW DISEASE

Ebola virus disease is a severe hemorrhagic fever caused by negative-sense single-stranded RNA viruses classified by the International Committee on Taxonomy of Viruses as belonging to the genus Ebolavirus in the family Filoviridae. Filoviruses get their name from the Latin filum, or thread-like structure.

The family Filoviridae was discovered in 1967 after inadvertent importation of infected monkeys from Uganda into Yugoslavia and Marburg, Germany. Outbreaks of severe illness occurred in workers at a vaccine plant who came into direct contact with the animals by killing them, removing their kidneys, or preparing primary cell cultures for polio vaccine production.

Ebola virus was discovered in 1976 by Peter Piot, who was working at the Institute of Tropical Medicine in Antwerp, Belgium. The blood of a Belgian woman who had been working in what is now the Democratic Republic of the Congo (formerly Zaire) had been sent to the institute; she and Mabalo Lokela, a school headmaster and the first recorded victim of Ebola virus, had been working near Yambuku, about 96 km from the Ebola River.

Before the 2014 outbreak, all known outbreaks had caused fewer than 2,400 cases across a dozen African countries over 3 decades.

Five species of Ebola virus

The genus Ebolavirus contains five species, each associated with a consistent case-fatality rate and a more or less well-identified endemic area.¹

Zaire ebolavirus was recognized in 1976; it has caused multiple outbreaks, with high case-fatality rates.

Sudan ebolavirus was seen first in the 1970s; it has a 50% case-fatality rate.

Tai Forest ebolavirus has been found in only one person, an ethologist working with deceased chimpanzees.

Bundibugyo ebolavirus emerged in 2007 and has a 30% case-fatality rate.

Reston ebolavirus is maintained in an animal reservoir in the Philippines and is not found in Africa. It caused an outbreak of lethal infection in macaques imported into the United States in 1989. There is evidence that Reston ebolavirus can cause asymptomatic infection in humans. None of the caretakers of the macaques became ill, nor did farmers working with infected pigs, although both groups seroconverted.

A reservoir in bats?

A reservoir in nonhuman primates was initially suspected. However, studies subsequently showed that monkeys are susceptible to rapidly lethal filoviral disease, precluding any role as a host for persistent viral infection. It is likely that Ebola virus is maintained in small animals that serve as a source of infection for both humans and wild primates. A prominent suspect is fruit bats, which are consumed in soup in West Africa.

Transmission is person-to-person or nosocomial

Ebola virus is transmitted by direct contact with body fluids such as blood, urine, sweat, vomitus, semen, and breast milk. Filoviruses can initiate infection via ingestion, inhalation (although probably not Ebola), or passage through breaks in the skin. Droplet inoculation into the mouth or eyes has been shown to result from inadvertent transfer of virus from contaminated hands. Patients transmit the virus while febrile and through later stages of disease, as well as postmortem through contact with the body during funeral preparations. The virus has been isolated in semen for as many as 61 days after illness onset.

One primary human case generates only one to three secondary cases on average, but the case-fatality rate is high

Ebola virus can also be spread nosocomially. In 1976, a 44-year-old teacher sought care for fever at the Yambuku Mission Hospital. He was given parenteral chloroquine as empiric treatment for presumed malaria, which was routine for all febrile patients. However, he had unrecognized Ebola virus infection. Moreover, syringes were rinsed in the same pan of water and reused, which spread the infection to nearly 100 people, all of whom developed fulminant Ebola virus disease and died. Infection then spread to family caregivers, the hospital staff, and those who prepared the bodies for burial.

Nosocomial transmission was also responsible for an outbreak of Lake Victoria Marburg virus in Uige Province in northern Angola in 2005, with 374 putative cases and 329 deaths. When teams from Médecins Sans Frontières started setting up the Marburg ward, there were five patients with hemorrhagic fever in a makeshift isolation room in the hospital, together with corpses that the hospital staff had been too afraid to remove. Healers found in many rural African communities were administering injections in homes or in makeshift clinics with reused needles or syringes.²

There is no evidence that filoviruses are carried by mosquitoes or other biting arthropods. Also, the risk of transmission via fomites appears to be low when currently recommended infection-control guidelines for the viral hemorrhagic fevers are followed.³ One primary human case generates only one to three secondary cases on average.

EBOLA IS AN IMMUNODEFICIENCY VIRUS

The main targets of infection are endothelial cells, mononuclear phagocytes, and hepatocytes. Ebola virus replicates at an unusually high rate. Macrophages infected with Zaire ebolavirus produce tumor necrosis factor alpha, interleukin (IL) 1 beta, IL-6, macrophage chemotactic protein 1, and nitric oxide. Virus-infected macrophages synthesize cell-surface tissue factor, triggering the extrinsic coagulation pathway.

Ebola is an immunodeficiency virus. Dendritic cells, which initiate adaptive immune responses, are a major site of filoviral replication. Infected cells cannot present antigens to naïve lymphocytes. Patients who die of Ebola virus disease do not develop antibodies to the virus. Lymphocytes remain uninfected, but undergo “bystander” apoptosis induced by inflammatory mediators.

CLINICAL MANIFESTATIONS

The incubation period is generally 5 to 7 days (range 2 to 28 days), during which the patient is not infectious. Symptoms begin abruptly, with fever, chills, general malaise, weakness, severe headache, and myalgia. By the time of case detection in West Africa, most patients also had nausea, vomiting, diarrhea, and abdominal pain. Once symptoms arise, patients have high levels of the virus in their blood and fluids and are infectious. Hemorrhagic symptoms have apparently been uncommon in West Africa, occurring in 1.0% to 5.7%, but “unexplained bleeding” has been documented in 18% of cases.⁴ Among those in whom the disease enters its hemorrhagic terminal phase, there is characteristic internal and subcutaneous bleeding, vomiting of blood, and subconjunctival hemorrhage.⁴

Laboratory findings include lymphocytopenia (often with counts as low as 1.0 × 10⁹/L), thrombocytopenia (with counts in the range of 50 to 100 × 10⁹/L), elevated aminotransferase levels (including aspartate aminotransferase levels 7 to 12 times higher than alanine aminotransferase in fatal cases), low total protein (due to capillary leak), and disseminated intravascular coagulation. Those who survive begin to improve in the second week, during which viremia resolves in association with the appearance of virus-specific antibodies.⁴

DIAGNOSIS

In symptomatic patients, Ebola virus infection is diagnosed by detection in blood or body fluids of viral antigens by enzyme-linked immunosorbent assay, or RNA sequences by reverse transcriptase polymerase chain reaction. The diagnosis is confirmed with cell culture (in a BSL-4 containment laboratory) showing characteristic viral particles by electron microscopy.

CARING FOR PATIENTS

The most detailed descriptions of the care of patients with Ebola virus disease have come from Dr. Bruce Ribner, of Emory University Hospital, in an October 2014 report of his experience caring for Ebola-infected patients at Emory University Hospital in Atlanta, GA.⁵ He described fluid losses of 5 to 10 L/day, profound hyponatremia, hypokalemia, and hypocalcemia, which were associated with cardiac arrhythmias and the need for intravenous and oral electrolyte repletion and hemodialysis. Intensive one-to-one nursing was critical, as was the coordination of many medical subspecialties. The Emory team arranged point-of-care testing near the unit and generally kept laboratory testing to a minimum. The team was surprised to learn that commercial carriers refused to transport specimens even when they were licensed for category A agents. Difficulties with the local water authority and waste disposal contractor required the hospital to dedicate an autoclave to process all materials used in clinical care.

TREATMENT: SUPPORTIVE AND EXPERIMENTAL

Treatment is supportive to maintain circulatory function and blood pressure and to correct coagulopathy. However, a variety of vaccines, antibodies, small-molecule agents, and antiviral agents are undergoing testing, mostly in animals at this point.

Vaccines. A therapeutic vaccine that worked only slightly was a live-attenuated recombinant vesicular stomatitis virus expressing Ebola virus transmembrane glycoproteins, which was tested in mice, guinea pigs, and rhesus macaques who had been exposed to Ebola virus.⁶

Incubation is about 5–7 days, during which the patient is not infectious

A preventive vaccine worked better. Stanley et al⁷ evaluated a replication-defective chimpanzee adenovirus 3-vectored vaccine that also contained Ebola virus glycoprotein. They gave macaques a single injection of this vaccine, and then 5 weeks later gave them a lethal dose of Ebola virus. All the vaccinated animals survived the infection, and half (2 of 4) survived when challenged 10 months later. With a prime-boost strategy (modified vaccinia virus Ankara, a poxvirus), all survived when challenged 10 months later.

KZ52, a neutralizing antibody, did not work. Oswald et al⁸ gave a human IgG monoclonal antibody against Zaire Ebola virus, designated KZ52, to four rhesus macaques, challenged them with the virus 24 hours later, and administered a second shot of KZ52 on day 4. All of them died.

ZMAb is a combination of three murine monoclonal antibodies, designated 1H3, 2G4, and 4G7. Ad-IFN is a human adenovirus, serotype 5, that expresses human interferon alpha. Qui et al⁹ gave ZMAb and Ad-IFN to macaques in several experiments. In experiment 1, eight macaques were infected and then were given ZMAb and Ad-IFN 3 days later, and ZMAb again on days 6 and 9. Seven of the eight survived. In a second experiment, Ad-IFN was given first, when the viral load was still less than the limit of detection of known assays, and then ZMAb was given upon detection of viremia and fever. Two of four macaques survived. Control animals had undetectable levels of IgG, whereas Ebola virus GP–specific IgG levels were detected in all survivors. IFN-gamma ELISpots showed high EBOV-GP–specific T-cell response in all survivors.

ZMapp is another cocktail of monoclonal antibodies, containing two from ZMab (2G4 and 4G7), plus a third, c13C6. In experiments in rhesus macaques, three groups of six animals each received three doses of ZMapp at varying times after being infected with Ebola virus: at 3, 6, and 9 days; at 4, 7, and 10 days, and at 5, 8, and 11 days. All 18 macaques treated with ZMapp survived. Thus, Zmapp extended the treatment window to 5 days postexposure.¹⁰ One of the American health care workers who contracted Ebola virus in Liberia received this medication.

HSPA5-PMO. Endoplasmic reticulum chaperone heat shock 70 kDa protein 5 (HSPA5) is instrumental in the maturation of envelope proteins in hepatitis C and influenza A virus. It plays a role in viral entry for coxsackievirus A9 and dengue virus serotype 2, and it may be involved in Ebola viral budding. Phosphorodiamidate morpholino oligomers (PMOs) are a class of antisense DNA nucleotide analogs.

Reid et al¹¹ reported that mice treated with HSPA5–PMO were completely protected from lethal Ebola challenge. Therefore, HSPA5 appears to be a promising target for the development of antifilovirus countermeasures.

Favipiravir, an antiviral agent also known as T-705, is a pyrazinecarboxamide derivative. Invented in 2002 by Toyama Chemicals as an inhibitor of influenza virus replication, it acts as a nucleotide analog, selectively inhibiting the viral RNA-dependent RNA polymerase, or causes lethal mutagenesis upon incorporation into the virus RNA. Favipiravir suppresses Ebola virus replication by 4 log₁₀ units in cell culture.¹²

Mice were challenged with intranasal inoculation of 1,000 focus-forming units of Ebola virus diluted in phosphate-buffered saline. Until the first day of treatment (postinfection day 6), all mice in the T-705 group lost weight similarly to control mice, developed viremia, and showed elevated serum levels of aspartate aminotransferase and alanine aminotransferase. Within 4 days of T-705 treatment (post-infection day 10), the animals had cleared the virus from blood. Surviving mice developed Ebola virus-specific antibodies and CD8+ T cells specific for the viral nucleoprotein.¹²

The authors hypothesized that suppression of virus replication by T-705 allowed the host to mount a virus-specific adaptive immune response, and concluded that T-705 was 100% effective in the treatment of Zaire Ebola virus infection up to postinfection day 6 but was hardly beneficial at the terminal stage of disease.¹² Of note, favipiravir is undergoing phase 2 and phase 3 trials as an anti-influenza agent in Japan.

THE CURRENT OUTBREAK

The current outbreak is with Zaire ebolavirus. It seems to have started in a 2-year-old child who died in Meliandou in Guéckédou Prefecture, Guinea, on December 6, 2013. On March 21, 2014, the Guinea Ministry of Health reported the outbreak of an illness characterized by fever, severe diarrhea, vomiting, and a high case-fatality rate (59%) in 49 persons. On May 25, 2014, Kenema Government Hospital confirmed the first case of Ebola virus disease in Sierra Leone, probably brought there by a traditional healer who had treated Ebola patients from Guinea. Tracing led to 13 additional cases—all women who attended the burial.¹³

The Center for Systems Biology at Harvard University and the Broad Institute of Massachusetts Institute of Technology generated 99 Ebola virus genome sequences from 78 patients with confirmed disease, representing more than 70% of the patients diagnosed with the disease in Sierra Leone from May to mid-June 2014. They found genetic similarity across the sequenced 2014 samples, suggesting a single transmission from the natural reservoir, followed by human-to-human transmission during the outbreak. Continued human-reservoir exposure is unlikely to have contributed to the growth of this epidemic.¹⁴

As of October 14, 2014, there were 8,914 suspected and confirmed cases of Ebola virus infection, and 4,477 deaths.¹⁵

Favipiravir is undergoing phase 2 and phase 3 trials as an anti-influenza agent in Japan

But how did Zaire Ebola virus make the 2,000-mile trek from Central Africa to Guinea in West Africa? There are two possibilities: it has always been present in the region but we just never noticed, or it was recently introduced. Bayesian phylogenetic analyses and sequence divergence studies suggest the virus has been present in bat populations in Guinea without previously infecting humans.

Why Guinea and why Guéckédou? Guinea is one of the poorest countries in the world, ranking 178th of 187 countries on the Human Development Index of the United Nations Development Programme, just behind Liberia (174th) and Sierra Leone (177th). In Guinea, the life expectancy is 56 years and the gross national income per capita is $440. The region has been systematically plundered and the forest decimated by clear-cut logging, leaving the Guinea Forest Region largely deforested, resulting in increased contact between humans and the small animals that serve as the source of infection.¹

LIMITED CAPACITY, EVEN IN THE UNITED STATES

A few hospitals in the United States have dedicated units to handle serious infectious diseases such as Ebola: Emory University Hospital; Nebraska Medicine in Omaha; Providence St. Patrick Hospital in Missoula, MT; and the National Institutes of Health in Bethesda, MD. However, in total they have only 19 beds.

QUESTIONS, ANSWERS—AND MORE QUESTIONS

(The following is from a question-and-answer discussion that followed Dr. Brizendine’s Grand Rounds presentation.)

Q: Are there any differences between survivors and those who die of the disease? A: We do not know. Patient survival depends on early recognition and supportive care. There are disparities in the care of patients. Schieffelin et al¹⁶ analyzed the characteristics of patients who died or who survived in Sierra Leone and found that the mortality rate was higher in older patients and those with a higher viral load on presentation.

Q: Does the virus block production or release of interferon early in infection? A: Yes, it has been shown¹⁷ that Ebola virus protein VP24 inhibits signaling downstream of both interferon alpha/beta and interferon gamma by indirectly impairing the transport of a transcription factor termed STAT1. VP24 is also able to bind STAT1 directly. The resulting suppression of host interferon very early on in the incubation phase is key to the virulence of the virus.

Mutations are occurring but are not changing the characteristics of the Ebola virus

Q: Does infection with one of the viral species confer immunity from other species? A: No, there is no cross-immunity.

Q: How soon do patients test positive? A: About 5 days after exposure, when they develop a fever. At this time patients are highly viremic, which PCR can detect.

Q: Before the virus is detectable in the blood, where is it? A: The liver, endothelial cells, antigen-presenting cells, and adrenal glands.

Q: Do we really need to quarantine ill patients and health care workers returning from Africa, per CDC recommendations? A: We don’t know everything, and some people do make bad decisions, such as traveling while symptomatic. I support a period of observation, although confinement is not reasonable, as it may pose a disincentive to cooperation.

Q: What is the role of giving plasma from survivors? A: Dr. Kent Brantly (see American citizens infected with Ebola) received the blood of a 14-year-old who survived. We don’t know. It is not proved. It did not result in improvement in animal models.

Q: Is the bleeding caused by a mechanism similar to that in enterohemorrhagic Escherichia coli infection? A: No. That is a bacterial toxin, whereas this is more like disseminated intravascular coagulation, with an intrinsic pathway anticoagulation cascade.

Q: How long does the virus remain viable outside the body? A: In one study,¹⁸ Ebola virus could not be recovered from experimentally contaminated surfaces (plastic, metal or glass) at room temperature. In another in which it was dried onto a surface,¹⁹ Ebola virus survived in the dark for several hours between 20 and 25°C. When dried in tissue culture media onto glass and stored at 4°C, it has survived for over 50 days.

Q: How long does the virus remain in breast milk? A: We know it has been detected 15 days after disease onset and think possibly as late as 28 days from symptom onset.³

Q: How are people actually infected? A: I believe people get the virus on their hands and then touch their face, eyes, or mouth. If you are wearing personal protective equipment, it must occur while doffing the equipment.

Q: Could we increase the sensitivity of the test so that we could detect the virus before the onset of symptoms? A: In theory it may be possible. The virus is somewhere in the body during the incubation period. Perhaps we could sample the right compartment in an enriched mononuclear cell line.

Q: When can patients who recover resume their normal activities? A: After their viral load returns to 0, I would still advise abstaining from unprotected sex and from breastfeeding for a few months. but as for other activities, no special precautions are needed.

Q: Does the virus appear to be mutating at a high rate? A: Looking back to 2004, mutations are occurring, but there is no sign that any of these mutations has contributed to the size of the outbreak by changing the characteristics of the Ebola virus. Can it become aerosolized? It has been suggested that the virus that caused the outbreak separated from those that caused past Ebola outbreaks but does not seem to be affecting the spread or efficacy of experimental drugs and vaccines. So, even though it is an RNA virus and mutations are occurring, no serious changes have emerged.¹⁴

BACK TO OUR PATIENT

The differential diagnosis for the patient described at the beginning of this paper includes travelers’ diarrhea, malaria, typhoid fever, yellow fever, meningococcal disease … and Ebola virus disease, although this is much less likely in view of the epidemiology and incubation period of this disease. When his stool was tested by enzyme immunoassay and culture, it was found to be positive for Campylobacter. He recovered with oral rehydration.

A 50-year-old man who returned from a business trip to Nigeria 24 days ago presents with complaints of the sudden onset of fever, diarrhea, myalgia, and headache. He reports 10 bowel movements per day and has seen bloody stools.

During his trip he flew in to Murtala Muhammed International Airport in Lagos, ate meals only in his hotel, and attended meetings in Lagos central business district. He had no exposure to animals, mosquitoes, ticks, or sick people, and no sexual activity. After returning home, he felt well for the first 3 weeks.

The patient has a history of hypertension. He does not smoke, drink alcohol, or use injection drugs. He is married, works with commercial banks and financial institutions, and lives in Cleveland, OH.

On physical examination his temperature is 100.0˚F (37.8˚C), pulse 98, respirations 15, blood pressure 105/70 mm Hg, and weight 78 kg (172 lb). He appears comfortable but is a little diaphoretic. His abdomen is tender to palpation in the epigastrium and slightly to the right; he has no signs of peritonitis. His skin is without rash, bleeding, or bruising. The remainder of the examination is normal.

His white blood cell count is 17 × 10⁹/L, hemoglobin 15 g/dL, hematocrit 41%, and platelet count 172 × 10⁹/L. His sodium level is 126 mmol/L, potassium 3.8 mmol/L, chloride 95 mmol/L, carbon dioxide 20 mmol/L, blood urea nitrogen 11 mg/dL, creatinine 0.7 mg/dL, and glucose 130 mg/dL. His aminotransferase and alkaline phosphatase levels are normal.

Could this patient have Ebola virus disease?

With Ebola virus disease on the rise in West Africa, physicians who encounter patients like this one need to include it in the differential diagnosis. Because the disease is new, many questions are raised for which we as yet have no answers. Here, I will review what we know and do not know in an effort to remove some of the fear and uncertainty.

A NEW DISEASE

Ebola virus disease is a severe hemorrhagic fever caused by negative-sense single-stranded RNA viruses classified by the International Committee on Taxonomy of Viruses as belonging to the genus Ebolavirus in the family Filoviridae. Filoviruses get their name from the Latin filum, or thread-like structure.

The family Filoviridae was discovered in 1967 after inadvertent importation of infected monkeys from Uganda into Yugoslavia and Marburg, Germany. Outbreaks of severe illness occurred in workers at a vaccine plant who came into direct contact with the animals by killing them, removing their kidneys, or preparing primary cell cultures for polio vaccine production.

Ebola virus was discovered in 1976 by Peter Piot, who was working at the Institute of Tropical Medicine in Antwerp, Belgium. The blood of a Belgian woman who had been working in what is now the Democratic Republic of the Congo (formerly Zaire) had been sent to the institute; she and Mabalo Lokela, a school headmaster and the first recorded victim of Ebola virus, had been working near Yambuku, about 96 km from the Ebola River.

Before the 2014 outbreak, all known outbreaks had caused fewer than 2,400 cases across a dozen African countries over 3 decades.

Five species of Ebola virus

The genus Ebolavirus contains five species, each associated with a consistent case-fatality rate and a more or less well-identified endemic area.¹

Zaire ebolavirus was recognized in 1976; it has caused multiple outbreaks, with high case-fatality rates.

Sudan ebolavirus was seen first in the 1970s; it has a 50% case-fatality rate.

Tai Forest ebolavirus has been found in only one person, an ethologist working with deceased chimpanzees.

Bundibugyo ebolavirus emerged in 2007 and has a 30% case-fatality rate.

Reston ebolavirus is maintained in an animal reservoir in the Philippines and is not found in Africa. It caused an outbreak of lethal infection in macaques imported into the United States in 1989. There is evidence that Reston ebolavirus can cause asymptomatic infection in humans. None of the caretakers of the macaques became ill, nor did farmers working with infected pigs, although both groups seroconverted.

A reservoir in bats?

A reservoir in nonhuman primates was initially suspected. However, studies subsequently showed that monkeys are susceptible to rapidly lethal filoviral disease, precluding any role as a host for persistent viral infection. It is likely that Ebola virus is maintained in small animals that serve as a source of infection for both humans and wild primates. A prominent suspect is fruit bats, which are consumed in soup in West Africa.

Transmission is person-to-person or nosocomial

Ebola virus is transmitted by direct contact with body fluids such as blood, urine, sweat, vomitus, semen, and breast milk. Filoviruses can initiate infection via ingestion, inhalation (although probably not Ebola), or passage through breaks in the skin. Droplet inoculation into the mouth or eyes has been shown to result from inadvertent transfer of virus from contaminated hands. Patients transmit the virus while febrile and through later stages of disease, as well as postmortem through contact with the body during funeral preparations. The virus has been isolated in semen for as many as 61 days after illness onset.

One primary human case generates only one to three secondary cases on average, but the case-fatality rate is high

Ebola virus can also be spread nosocomially. In 1976, a 44-year-old teacher sought care for fever at the Yambuku Mission Hospital. He was given parenteral chloroquine as empiric treatment for presumed malaria, which was routine for all febrile patients. However, he had unrecognized Ebola virus infection. Moreover, syringes were rinsed in the same pan of water and reused, which spread the infection to nearly 100 people, all of whom developed fulminant Ebola virus disease and died. Infection then spread to family caregivers, the hospital staff, and those who prepared the bodies for burial.

Nosocomial transmission was also responsible for an outbreak of Lake Victoria Marburg virus in Uige Province in northern Angola in 2005, with 374 putative cases and 329 deaths. When teams from Médecins Sans Frontières started setting up the Marburg ward, there were five patients with hemorrhagic fever in a makeshift isolation room in the hospital, together with corpses that the hospital staff had been too afraid to remove. Healers found in many rural African communities were administering injections in homes or in makeshift clinics with reused needles or syringes.²

There is no evidence that filoviruses are carried by mosquitoes or other biting arthropods. Also, the risk of transmission via fomites appears to be low when currently recommended infection-control guidelines for the viral hemorrhagic fevers are followed.³ One primary human case generates only one to three secondary cases on average.

EBOLA IS AN IMMUNODEFICIENCY VIRUS

The main targets of infection are endothelial cells, mononuclear phagocytes, and hepatocytes. Ebola virus replicates at an unusually high rate. Macrophages infected with Zaire ebolavirus produce tumor necrosis factor alpha, interleukin (IL) 1 beta, IL-6, macrophage chemotactic protein 1, and nitric oxide. Virus-infected macrophages synthesize cell-surface tissue factor, triggering the extrinsic coagulation pathway.

Ebola is an immunodeficiency virus. Dendritic cells, which initiate adaptive immune responses, are a major site of filoviral replication. Infected cells cannot present antigens to naïve lymphocytes. Patients who die of Ebola virus disease do not develop antibodies to the virus. Lymphocytes remain uninfected, but undergo “bystander” apoptosis induced by inflammatory mediators.

CLINICAL MANIFESTATIONS

The incubation period is generally 5 to 7 days (range 2 to 28 days), during which the patient is not infectious. Symptoms begin abruptly, with fever, chills, general malaise, weakness, severe headache, and myalgia. By the time of case detection in West Africa, most patients also had nausea, vomiting, diarrhea, and abdominal pain. Once symptoms arise, patients have high levels of the virus in their blood and fluids and are infectious. Hemorrhagic symptoms have apparently been uncommon in West Africa, occurring in 1.0% to 5.7%, but “unexplained bleeding” has been documented in 18% of cases.⁴ Among those in whom the disease enters its hemorrhagic terminal phase, there is characteristic internal and subcutaneous bleeding, vomiting of blood, and subconjunctival hemorrhage.⁴

Laboratory findings include lymphocytopenia (often with counts as low as 1.0 × 10⁹/L), thrombocytopenia (with counts in the range of 50 to 100 × 10⁹/L), elevated aminotransferase levels (including aspartate aminotransferase levels 7 to 12 times higher than alanine aminotransferase in fatal cases), low total protein (due to capillary leak), and disseminated intravascular coagulation. Those who survive begin to improve in the second week, during which viremia resolves in association with the appearance of virus-specific antibodies.⁴

DIAGNOSIS

In symptomatic patients, Ebola virus infection is diagnosed by detection in blood or body fluids of viral antigens by enzyme-linked immunosorbent assay, or RNA sequences by reverse transcriptase polymerase chain reaction. The diagnosis is confirmed with cell culture (in a BSL-4 containment laboratory) showing characteristic viral particles by electron microscopy.

CARING FOR PATIENTS

The most detailed descriptions of the care of patients with Ebola virus disease have come from Dr. Bruce Ribner, of Emory University Hospital, in an October 2014 report of his experience caring for Ebola-infected patients at Emory University Hospital in Atlanta, GA.⁵ He described fluid losses of 5 to 10 L/day, profound hyponatremia, hypokalemia, and hypocalcemia, which were associated with cardiac arrhythmias and the need for intravenous and oral electrolyte repletion and hemodialysis. Intensive one-to-one nursing was critical, as was the coordination of many medical subspecialties. The Emory team arranged point-of-care testing near the unit and generally kept laboratory testing to a minimum. The team was surprised to learn that commercial carriers refused to transport specimens even when they were licensed for category A agents. Difficulties with the local water authority and waste disposal contractor required the hospital to dedicate an autoclave to process all materials used in clinical care.

TREATMENT: SUPPORTIVE AND EXPERIMENTAL

Treatment is supportive to maintain circulatory function and blood pressure and to correct coagulopathy. However, a variety of vaccines, antibodies, small-molecule agents, and antiviral agents are undergoing testing, mostly in animals at this point.

Vaccines. A therapeutic vaccine that worked only slightly was a live-attenuated recombinant vesicular stomatitis virus expressing Ebola virus transmembrane glycoproteins, which was tested in mice, guinea pigs, and rhesus macaques who had been exposed to Ebola virus.⁶

Incubation is about 5–7 days, during which the patient is not infectious

A preventive vaccine worked better. Stanley et al⁷ evaluated a replication-defective chimpanzee adenovirus 3-vectored vaccine that also contained Ebola virus glycoprotein. They gave macaques a single injection of this vaccine, and then 5 weeks later gave them a lethal dose of Ebola virus. All the vaccinated animals survived the infection, and half (2 of 4) survived when challenged 10 months later. With a prime-boost strategy (modified vaccinia virus Ankara, a poxvirus), all survived when challenged 10 months later.

KZ52, a neutralizing antibody, did not work. Oswald et al⁸ gave a human IgG monoclonal antibody against Zaire Ebola virus, designated KZ52, to four rhesus macaques, challenged them with the virus 24 hours later, and administered a second shot of KZ52 on day 4. All of them died.

ZMAb is a combination of three murine monoclonal antibodies, designated 1H3, 2G4, and 4G7. Ad-IFN is a human adenovirus, serotype 5, that expresses human interferon alpha. Qui et al⁹ gave ZMAb and Ad-IFN to macaques in several experiments. In experiment 1, eight macaques were infected and then were given ZMAb and Ad-IFN 3 days later, and ZMAb again on days 6 and 9. Seven of the eight survived. In a second experiment, Ad-IFN was given first, when the viral load was still less than the limit of detection of known assays, and then ZMAb was given upon detection of viremia and fever. Two of four macaques survived. Control animals had undetectable levels of IgG, whereas Ebola virus GP–specific IgG levels were detected in all survivors. IFN-gamma ELISpots showed high EBOV-GP–specific T-cell response in all survivors.

ZMapp is another cocktail of monoclonal antibodies, containing two from ZMab (2G4 and 4G7), plus a third, c13C6. In experiments in rhesus macaques, three groups of six animals each received three doses of ZMapp at varying times after being infected with Ebola virus: at 3, 6, and 9 days; at 4, 7, and 10 days, and at 5, 8, and 11 days. All 18 macaques treated with ZMapp survived. Thus, Zmapp extended the treatment window to 5 days postexposure.¹⁰ One of the American health care workers who contracted Ebola virus in Liberia received this medication.

HSPA5-PMO. Endoplasmic reticulum chaperone heat shock 70 kDa protein 5 (HSPA5) is instrumental in the maturation of envelope proteins in hepatitis C and influenza A virus. It plays a role in viral entry for coxsackievirus A9 and dengue virus serotype 2, and it may be involved in Ebola viral budding. Phosphorodiamidate morpholino oligomers (PMOs) are a class of antisense DNA nucleotide analogs.

Reid et al¹¹ reported that mice treated with HSPA5–PMO were completely protected from lethal Ebola challenge. Therefore, HSPA5 appears to be a promising target for the development of antifilovirus countermeasures.

Favipiravir, an antiviral agent also known as T-705, is a pyrazinecarboxamide derivative. Invented in 2002 by Toyama Chemicals as an inhibitor of influenza virus replication, it acts as a nucleotide analog, selectively inhibiting the viral RNA-dependent RNA polymerase, or causes lethal mutagenesis upon incorporation into the virus RNA. Favipiravir suppresses Ebola virus replication by 4 log₁₀ units in cell culture.¹²

Mice were challenged with intranasal inoculation of 1,000 focus-forming units of Ebola virus diluted in phosphate-buffered saline. Until the first day of treatment (postinfection day 6), all mice in the T-705 group lost weight similarly to control mice, developed viremia, and showed elevated serum levels of aspartate aminotransferase and alanine aminotransferase. Within 4 days of T-705 treatment (post-infection day 10), the animals had cleared the virus from blood. Surviving mice developed Ebola virus-specific antibodies and CD8+ T cells specific for the viral nucleoprotein.¹²

The authors hypothesized that suppression of virus replication by T-705 allowed the host to mount a virus-specific adaptive immune response, and concluded that T-705 was 100% effective in the treatment of Zaire Ebola virus infection up to postinfection day 6 but was hardly beneficial at the terminal stage of disease.¹² Of note, favipiravir is undergoing phase 2 and phase 3 trials as an anti-influenza agent in Japan.

THE CURRENT OUTBREAK

The current outbreak is with Zaire ebolavirus. It seems to have started in a 2-year-old child who died in Meliandou in Guéckédou Prefecture, Guinea, on December 6, 2013. On March 21, 2014, the Guinea Ministry of Health reported the outbreak of an illness characterized by fever, severe diarrhea, vomiting, and a high case-fatality rate (59%) in 49 persons. On May 25, 2014, Kenema Government Hospital confirmed the first case of Ebola virus disease in Sierra Leone, probably brought there by a traditional healer who had treated Ebola patients from Guinea. Tracing led to 13 additional cases—all women who attended the burial.¹³

The Center for Systems Biology at Harvard University and the Broad Institute of Massachusetts Institute of Technology generated 99 Ebola virus genome sequences from 78 patients with confirmed disease, representing more than 70% of the patients diagnosed with the disease in Sierra Leone from May to mid-June 2014. They found genetic similarity across the sequenced 2014 samples, suggesting a single transmission from the natural reservoir, followed by human-to-human transmission during the outbreak. Continued human-reservoir exposure is unlikely to have contributed to the growth of this epidemic.¹⁴

As of October 14, 2014, there were 8,914 suspected and confirmed cases of Ebola virus infection, and 4,477 deaths.¹⁵

Favipiravir is undergoing phase 2 and phase 3 trials as an anti-influenza agent in Japan

But how did Zaire Ebola virus make the 2,000-mile trek from Central Africa to Guinea in West Africa? There are two possibilities: it has always been present in the region but we just never noticed, or it was recently introduced. Bayesian phylogenetic analyses and sequence divergence studies suggest the virus has been present in bat populations in Guinea without previously infecting humans.

Why Guinea and why Guéckédou? Guinea is one of the poorest countries in the world, ranking 178th of 187 countries on the Human Development Index of the United Nations Development Programme, just behind Liberia (174th) and Sierra Leone (177th). In Guinea, the life expectancy is 56 years and the gross national income per capita is $440. The region has been systematically plundered and the forest decimated by clear-cut logging, leaving the Guinea Forest Region largely deforested, resulting in increased contact between humans and the small animals that serve as the source of infection.¹

LIMITED CAPACITY, EVEN IN THE UNITED STATES

A few hospitals in the United States have dedicated units to handle serious infectious diseases such as Ebola: Emory University Hospital; Nebraska Medicine in Omaha; Providence St. Patrick Hospital in Missoula, MT; and the National Institutes of Health in Bethesda, MD. However, in total they have only 19 beds.

QUESTIONS, ANSWERS—AND MORE QUESTIONS

(The following is from a question-and-answer discussion that followed Dr. Brizendine’s Grand Rounds presentation.)

Q: Are there any differences between survivors and those who die of the disease? A: We do not know. Patient survival depends on early recognition and supportive care. There are disparities in the care of patients. Schieffelin et al¹⁶ analyzed the characteristics of patients who died or who survived in Sierra Leone and found that the mortality rate was higher in older patients and those with a higher viral load on presentation.

Q: Does the virus block production or release of interferon early in infection? A: Yes, it has been shown¹⁷ that Ebola virus protein VP24 inhibits signaling downstream of both interferon alpha/beta and interferon gamma by indirectly impairing the transport of a transcription factor termed STAT1. VP24 is also able to bind STAT1 directly. The resulting suppression of host interferon very early on in the incubation phase is key to the virulence of the virus.

Mutations are occurring but are not changing the characteristics of the Ebola virus

Q: Does infection with one of the viral species confer immunity from other species? A: No, there is no cross-immunity.

Q: How soon do patients test positive? A: About 5 days after exposure, when they develop a fever. At this time patients are highly viremic, which PCR can detect.

Q: Before the virus is detectable in the blood, where is it? A: The liver, endothelial cells, antigen-presenting cells, and adrenal glands.

Q: Do we really need to quarantine ill patients and health care workers returning from Africa, per CDC recommendations? A: We don’t know everything, and some people do make bad decisions, such as traveling while symptomatic. I support a period of observation, although confinement is not reasonable, as it may pose a disincentive to cooperation.

Q: What is the role of giving plasma from survivors? A: Dr. Kent Brantly (see American citizens infected with Ebola) received the blood of a 14-year-old who survived. We don’t know. It is not proved. It did not result in improvement in animal models.

Q: Is the bleeding caused by a mechanism similar to that in enterohemorrhagic Escherichia coli infection? A: No. That is a bacterial toxin, whereas this is more like disseminated intravascular coagulation, with an intrinsic pathway anticoagulation cascade.

Q: How long does the virus remain viable outside the body? A: In one study,¹⁸ Ebola virus could not be recovered from experimentally contaminated surfaces (plastic, metal or glass) at room temperature. In another in which it was dried onto a surface,¹⁹ Ebola virus survived in the dark for several hours between 20 and 25°C. When dried in tissue culture media onto glass and stored at 4°C, it has survived for over 50 days.

Q: How long does the virus remain in breast milk? A: We know it has been detected 15 days after disease onset and think possibly as late as 28 days from symptom onset.³

Q: How are people actually infected? A: I believe people get the virus on their hands and then touch their face, eyes, or mouth. If you are wearing personal protective equipment, it must occur while doffing the equipment.

Q: Could we increase the sensitivity of the test so that we could detect the virus before the onset of symptoms? A: In theory it may be possible. The virus is somewhere in the body during the incubation period. Perhaps we could sample the right compartment in an enriched mononuclear cell line.

Q: When can patients who recover resume their normal activities? A: After their viral load returns to 0, I would still advise abstaining from unprotected sex and from breastfeeding for a few months. but as for other activities, no special precautions are needed.

Q: Does the virus appear to be mutating at a high rate? A: Looking back to 2004, mutations are occurring, but there is no sign that any of these mutations has contributed to the size of the outbreak by changing the characteristics of the Ebola virus. Can it become aerosolized? It has been suggested that the virus that caused the outbreak separated from those that caused past Ebola outbreaks but does not seem to be affecting the spread or efficacy of experimental drugs and vaccines. So, even though it is an RNA virus and mutations are occurring, no serious changes have emerged.¹⁴

BACK TO OUR PATIENT

The differential diagnosis for the patient described at the beginning of this paper includes travelers’ diarrhea, malaria, typhoid fever, yellow fever, meningococcal disease … and Ebola virus disease, although this is much less likely in view of the epidemiology and incubation period of this disease. When his stool was tested by enzyme immunoassay and culture, it was found to be positive for Campylobacter. He recovered with oral rehydration.

More than 30 years into the human immunodeficiency virus (HIV) epidemic, our understanding of the needs of women living with this virus continues to evolve. In the early years of the epidemic, managing HIV was all about preventing death and treating opportunistic infections. But now it is also about enabling patients to live long, healthy, and productive lives and preventing new HIV infections. In women, these goals can only be achieved by paying careful attention to sex-specific issues.

See related editorial

As a result of longer survival, HIV-infected persons are increasingly developing common health problems that also affect the general population and that require screening, management, and monitoring by primary care providers. Because people infected with HIV are typically seen by both an HIV specialist and a primary care provider, HIV specialists need to be familiar with primary care issues and primary care providers need to be familiar with HIV care recommendations in order to provide optimal care.

AFRICAN AMERICAN WOMEN BEAR A DISPROPORTIONATE BURDEN

In the United States, HIV was first reported in women in 1983 among those who had been steady sexual partners of males with acquired immune deficiency syndrome.¹ Although men with HIV still outnumber women, the number of women with HIV has increased rapidly. At the end of 2010 an estimated one in four people with HIV in the United States was female.²

African American women bear a disproportionate burden of the disease (Table 1).³ In 2010, women accounted for an estimated 9,500 (20%) of the approximately 45,000 new infections occurring in the United States. Of these newly infected women, 64% were black, 18% were white, and 15% were Hispanic. Yet blacks make up only about 12% of the US population, whites make up 68%, and Hispanics 14%.

Regardless of race or ethnicity, unprotected heterosexual contact is the most common mode of transmission of HIV in women.²

Although the overall rates of HIV infection in the United States are relatively low, certain areas of the country have rates similar to those in sub-Saharan Africa, where most HIV-infected people reside.⁴ The HIV Prevention Trials Network found that the incidence of HIV infection in US women living in these “hot spots,” with high rates of poverty and HIV, was 0.32% per year. Compare this with the 2009 estimate of HIV incidence in the general population of US black women of similar age (0.05% per year) and the adult incidence rates in Congo (0.28% per year) and Kenya (0.53% per year).⁵ To better understand the epidemiology of HIV infection in women and concentrate our prevention efforts, we need to focus on these hot spots.

Misinformation abounds in these hot spots, as does disease. In a survey of residents of the South Side Chicago Housing Authority facilities,⁶ many were aware that effective antiretroviral therapy existed, but one-fourth thought that there was an effective HIV vaccine, and 13% thought there was a cure.

In the early years, an HIV diagnosis was essentially a death sentence. Samji et al⁷ estimated that life expectancy of patients who were prescribed antiretroviral therapy in the United States and Canada increased from 36.1 years in 2000–2002 to 51.4 years in 2006–2007, with the greatest increases in those who started with a baseline CD4 count above 350 cells/mm³. Now, a 20-year-old HIV-positive person with a CD4 count greater than 350 cells/mm³ can expect to live into his or her early 70s.

But not all patients achieve these benefits. In 2009, despite major advances in diagnosis and treatment, HIV was the fourth leading cause of death among African American women ages 25 to 44, causing about 800 deaths, or 9% of all deaths in this group.⁸

TEST ALL, UNLESS THEY OPT OUT

Testing is vital in efforts to prevent and treat HIV infection. In 2006, the US Centers for Disease Control and Prevention (CDC) recommended that everyone between the ages of 13 and 64 be screened for HIV regardless of risk.⁹

The CDC recommends an opt-out strategy.⁹ Rather than ask a patient whether he or she wants to be tested for HIV, the provider says something like, “I advise all of my patients to have an HIV test; as long as you have no objection, we will send you to the lab to have it done.” This approach reduces barriers to HIV testing by eliminating pretest counseling and by making HIV testing routine and the standard of care. Separate consent is not required—clinicians just need to document whether the patient has accepted or declined the test.

Testing should be offered at least once and can be done in any health care setting, including primary care offices and clinics, emergency rooms, health departments, and urgent care centers.⁹ Patients at higher risk (injection drug users and their sex partners; people who exchange sex for money or drugs; sex partners of HIV-infected people; men who have sex with men; and heterosexuals who themselves or whose sex partners have had more than one sex partner since their most recent HIV test) should receive repeat screening annually.

HIV testing should also be offered to all pregnant women at entry into care and again in the third trimester. This strategy is cost-effective even in areas of low prevalence.⁹ Since 2006, other professional organizations have made HIV testing recommendations as well (Table 2).^9–12

A cost-effectiveness analysis suggested that routine opt-out testing is economically justified if the prevalence of HIV is greater than 0.2%.¹³

HIV-POSITIVE WOMEN NEED ROUTINE GYNECOLOGIC CARE

It is important for women with HIV to receive routine gynecologic care. Women with HIV have gynecologic problems similar to those of all women; however, they may be more vulnerable to certain conditions such as human papillomavirus (HPV) infection, which may be related to HIV disease or associated immunosuppression. In addition, pregnancy and family planning pose special challenges in this group.¹⁴

Cervical cancer screening

Effective screening and timely treatment of precancerous cervical lesions are key in preventing cervical cancer in women with or without HIV.

Persistent infection with HPV is necessary for the development of precancerous lesions as well as invasive cervical cancer. Most new cases of HPV infection in the general population resolve spontaneously within 2 years. However, in HIV-infected women, HPV infection is more likely to persist and progress to precancerous lesions of the cervix. This association is strongest in women with more compromised immune function as reflected by low CD4 cell counts and high viral loads.¹⁴ Women with HIV have higher rates of infection with high-risk HPV strains and of cervical intraepithelial neoplasia compared with their HIV-negative counterparts.¹⁴ The incidence of cervical cancer is five to six times higher in HIV-infected women in the United States than in the general population.¹⁵

According to guidelines from the Infectious Diseases Society of America,¹⁶ the American College of Obstetricians and Gynecologists,¹⁰ the CDC,¹⁷ and the American Cancer Society,¹⁸ all HIV-infected women should undergo cervical Papanicolaou (Pap) screening upon initiation into care, and this test should be repeated at 6 months and then annually if the results are normal. Patients with abnormalities on the Pap test should undergo colposcopy and, possibly, also biopsy. These abnormalities include atypical squamous cells of unknown significance and higher-grade lesions.¹⁶

Nearly one-fourth of HIV-positive women do not receive annual Pap smears despite engagement in care.¹⁹ This is unacceptable, because half of the cases of cervical cancer diagnosed in the United States are in women who never received appropriate screening, and an additional 10% are in women who have not been screened in the previous 5 years.¹⁹

In HIV-infected women who have had a total hysterectomy, whether to continue Pap testing depends on their history before the surgery. Continued vaginal Pap smear screening is recommended after hysterectomy (including removal of the cervix) in HIV-infected women who have a history of cervical intraepithelial neoplasia grades 2 or 3 or invasive cancer.^10,17,20

TREATING HIV IN WOMEN: SPECIAL CONSIDERATIONS

Because it is not yet possible to eradicate the HIV virus, the goals of antiretroviral therapy are to reduce HIV-associated morbidity and mortality, to restore and preserve immune function, to suppress viral load, and to prevent sexual and, in women, perinatal transmission of the virus.²¹

Antiretroviral therapy is recommended for all HIV-infected patients regardless of the CD4 count, although the strength of recommendation is weaker with higher CD4 counts (Table  3).²¹ The recommendations for starting antiretroviral therapy and the goals of treatment are the same for men and women. Table 4 summarizes the recommendations for adolescents and adults who are new to treatment.²¹ For women, additional factors that should be taken into account when considering a regimen include pregnancy potential and whether the drugs chosen for the regimen are considered safe in pregnancy.

Since the early years of the HIV epidemic, researchers have debated whether women attain the same benefits from antiretroviral therapy as men. US Food and Drug Administration investigators performed a meta-analysis of the efficacy outcomes in women in studies of antiretroviral drugs published between 2000 and 2008. They included randomized clinical trials reporting at least 48-week efficacy outcomes, with viral suppression defined as HIV RNA less than 50 copies/mL. The combined database included 40 trials of 16 drugs from 7 drug classes with a total of 20,328 HIV-positive participants. Overall, there were no clinically or statistically significant differences between the sexes in 48-week efficacy outcomes or in rates of trial discontinuation due to adverse events, loss to follow-up, or death.²²

Antiretroviral therapy may, however, cause different adverse effects in women than in men. For example:

Nevirapine, a nonnucleoside reverse transcriptase inhibitor, has been associated with the development of a rash and potentially life-threatening hepatotoxicity, more commonly in women than in men and at lower CD4 counts in women. This resulted in recommendations²¹ to avoid starting a nevirapine-containing regimen in women with CD4 counts greater than 250 cells/mm³ and in men with CD4 counts greater than 400 cells/mm³.

Ritonavir has been observed to cause a higher incidence of nausea and vomiting in women and a higher incidence of diarrhea in men. These are thought to be due to differences between men and women in weight and pharmacokinetics.²³

PRECONCEPTION COUNSELING FOR HIV-POSITIVE WOMEN

Preconception counseling is an essential component of both primary and preventive care and should be considered the standard of care for all women of reproductive age who have HIV.²⁴ Health care providers who fully understand the impact of HIV infection and associated comorbidities upon a woman’s reproductive health, fertility desires, and family planning needs are better prepared to assist in their patients’ reproductive health decisions.

The first few weeks of pregnancy are the most critical period in fetal development. During this time, a woman should be healthy and avoid any activities or substances that could cause adverse maternal or fetal outcomes. However, most patients present for prenatal care after this critical time period—thus the need for preconception counseling. Both the Infectious Diseases Society of America and the HIV Medicine Association recommend that all HIV-infected women of childbearing age be asked about their pregnancy plans and desires at the start of care and routinely thereafter.¹⁶

The goals of preconception care in women with HIV are to prevent unintended pregnancy, optimize maternal health before pregnancy, optimize pregnancy outcomes for mother and fetus, prevent perinatal HIV transmission, and prevent HIV transmission to an HIV-negative partner when trying to conceive.²⁴

Goal 1: Prevent unintended pregnancy

Nearly half of all pregnancies in the United States are unintended.²⁵ Moreover, the Women’s Interagency HIV Study²⁶ showed that women with HIV are underusing effective contraception. In the Medical Monitoring Project, 85% of the women who had been pregnant since being diagnosed with HIV said that at least one pregnancy was unplanned.²⁷

The consequences of unintended and unplanned pregnancies are serious and add significant burden to women, men, and families. Women who do not wish to become pregnant should be advised to use an effective method of contraception.

Contraception

Contraception use varies worldwide. Factors affecting its use include the methods available, patient choice, current health conditions, religious beliefs, perception of method effectiveness, and side effects.²⁴

The Women’s Interagency HIV Study evaluated trends in contraception use from 1998 to 2010. Condoms were the most common form of contraception, and their use changed little over time. Fewer than 15% of women with HIV used no contraception. The use of long-acting reversible contraception, including injectable progestins, implants, and intrauterine devices, which minimize the need for user adherence, increased among HIV-negative women but not among HIV-positive women.²⁸

The World Health Organization states that all available methods are safe for women with HIV except for spermicides with or without a diaphragm, as there is evidence linking the use of spermicides to an increased risk of HIV transmission (Table 5).²⁹

Some antiretroviral drugs may reduce the effectiveness of some contraceptives (Table 6); however, recommendations are based on pharmacokinetic studies, not on outcome studies. Condoms should be recommended not only to protect against pregnancy, but also to protect against sexually transmitted infections.

Goal 2: Optimize maternal health before pregnancy

Maternal health should be optimized before conceiving to reduce the risk of pregnancy-related morbidities and poor birth outcomes. This includes screening for other infections and ensuring that other comorbidities, such as hypertension, diabetes, substance abuse, and mental illness, are well managed with medications that are safe to use in pregnancy (Table 7).

Goal 3: Prevent perinatal HIV transmission

Educating the patient about perinatal transmission is a fundamental component of preconception counseling. Topics that need to be addressed are transmission risk and methods to reduce the risk, including not breastfeeding after delivery.

Goal 4: Prevent HIV transmission to an uninfected partner when trying to conceive

HIV-discordant couples who desire pregnancy should receive appropriate counseling about methods to minimize risk of transmission to the uninfected partner while trying to conceive. There are a number of effective methods and techniques, which are beyond the scope of this review. Key components of all methods are to screen for and treat sexually transmitted infections in both partners and to use effective antiretroviral therapy and attain maximal viral suppression in the HIV-positive partner.

Antiretroviral therapy for the HIV-infected partner significantly reduced the risk of HIV transmission by 96% in the HIV Prevention Trials Network 052 trial.³⁰ Of note: this reduction was the result of both risk-reduction counseling and antiretroviral therapy. This was the first randomized clinical trial to demonstrate that antiretroviral therapy in those with some preserved immune function (CD4 counts 350–500 cells/mm³) in conjunction with risk-reduction counseling can reduce HIV transmission to an uninfected partner.

Vaginal insemination without intercourse is another option for female-positive couples. The man ejaculates into a condom without spermicide, and the contents are introduced with a non-needle syringe or turkey baster. This can be done at home and confers no risk to the uninfected male partner.³¹ Chances of pregnancy can be maximized by insemination during the most fertile days of the menstrual cycle.

Preexposure prophylaxis combined with timed intercourse. In a study in Switzerland, the infected male partner was given antiretroviral therapy to suppress his viral load to less than 50 copies/mL for at least 6 months, and luteinizing hormone was measured every day in the urine of the noninfected female partner. When the urinary luteinizing hormone level reached a peak, the woman received a dose of tenofovir in the morning, the couple had unprotected intercourse, and the woman took a second dose the next morning. In 53 cases, none of the female partners seroconverted for HIV.³²

Health care providers need to document and update the relationship status, partner HIV status, and fertility desires of their HIV patients, both men and women, on a regular basis. Patient education should include awareness of referrals and options to help safely conceive when desired and achieve effective contraception when not.³³

WHEN HIV-POSITIVE WOMEN BECOME PREGNANT

Screening for HIV during pregnancy

The CDC recommends prenatal screening for HIV in the first trimester or at entry into prenatal care. A repeat HIV test should be offered in the third trimester for women at risk of acquiring HIV, for women who have signs or symptoms of early HIV infection, in health care settings where prenatal testing yields at least 1 case of HIV infection per 1,000 women screened, and in areas of high HIV incidence. If women present to labor and delivery with unknown HIV status, rapid HIV testing should be done.⁹

If a woman acquires HIV during pregnancy, the infection may not be detected and may be transmitted to the infant at birth. From 2002 to 2006 in New York State, 3,396 HIV-exposed babies were born. Of these, 9 (22%) of 41 infants born to mothers who acquired HIV during pregnancy became infected, compared with 1.8% of those born to mothers who acquired HIV before pregnancy. Maternal acquisition of HIV during pregnancy was documented in only 1.3% of perinatal HIV exposures, but it was associated with 9 (13.8%) of the 65 perinatal transmission cases.³⁴

Providers should be aware of the signs and symptoms of acute HIV infection and should have a low threshold for repeating HIV testing at any time during pregnancy. It has been estimated that 40% to 90% of patients with acute HIV infection experience fever, lymphadenopathy, pharyngitis, skin rash, myalgia, arthralgia, or other symptoms.³⁵ Providers often do not recognize acute HIV infection, however, because the symptoms are similar to those of other common illnesses. Also, some individuals with the condition have no symptoms.

Antiretroviral therapy during pregnancy

In a landmark study, AIDS Clinical Trial Group 076 demonstrated that zidovudine monotherapy given during pregnancy, labor, and delivery and to the newborn reduced the risk of HIV transmission to the infant by 67%, from 25% to 8%.³⁶ Other studies demonstrated that combination therapy further decreased the risk of HIV transmission to 1% to 2%.³⁷

The US Department of Health and Human Services recommends that all HIV-positive women who are pregnant receive effective combination antiretroviral therapy regardless of CD4 count to minimize the risk of mother-to-child transmission.³⁷

The goals of HIV treatment during pregnancy are to maintain the woman’s health, restore her immune system, suppress viral replication, and decrease the risk of perinatal transmission. The preferred antiretroviral therapy for pregnant women differs from that for nonpregnant women and is based on evolving experience and information about safety, efficacy, and tolerability in pregnancy (Table 8). A woman who presents for prenatal care on a suppressive regimen should continue that regimen as long as she can tolerate it because there is a risk of losing virologic control when switching regimens, and this may increase the risk of perinatal transmission.³⁷

Physiologic changes that occur during pregnancy may alter drug disposition, which could potentially lead to decreased drug exposure. Some of the changes include an increase in total body water, decreased protein binding, induction of hepatic metabolic pathways, and increased clearance of drugs eliminated by the kidneys.³⁸ These changes may be associated with incomplete virologic suppression, virologic failure, or development of drug resistance, so altered doses of some antiretroviral drugs or careful monitoring of viral load should be considered, particularly in the second and third trimester.

Delivery

Women who have a viral load greater than 1,000 copies/mL near the end of pregnancy should undergo a cesarean delivery at 38 weeks and, before surgery, should receive intravenous zidovudine to reduce the risk of perinatal transmission. For women with viral loads below the threshold of 1,000 copies/mL, there is no proven added benefit to cesarean delivery, and in this situation it should be performed only for standard obstetric indications. Antiretroviral regimens should be continued during labor.³⁷

HIV IN OLDER ADULTS

By 2015, approximately 50% of people with HIV will be over age 50.³⁹ Unfortunately, older people and their providers often underestimate their risk of acquiring HIV. Many older people are newly single and may engage in sexual activity with new partners. Also, older people may be reluctant to use condoms as the need for contraception is past.^40,41

Baseline HIV RNA levels tend to be higher and CD4 cell counts lower in patients diagnosed with HIV at older ages. These observations support previous ones that older HIV-infected patients may have advanced HIV disease at the time of diagnosis, perhaps in part due to delayed testing.⁴² Other possible factors are limited income, comorbid illness, polypharmacy, and insufficient data on drug interactions in the elderly.^41,42

A prompt diagnosis is important for older patients because HIV may accelerate aging, and aging may speed up HIV progression. Studies have shown that aging is associated with more rapid progression to AIDS, particularly among people who are older than 40 at seroconversion.⁴³ Other studies have reported that older patients have better virologic responses to antiretroviral therapy but have a blunted immune response, more AIDS-defining events, and a higher mortality rate than younger patients.⁴²

More than 30 years into the human immunodeficiency virus (HIV) epidemic, our understanding of the needs of women living with this virus continues to evolve. In the early years of the epidemic, managing HIV was all about preventing death and treating opportunistic infections. But now it is also about enabling patients to live long, healthy, and productive lives and preventing new HIV infections. In women, these goals can only be achieved by paying careful attention to sex-specific issues.

See related editorial

As a result of longer survival, HIV-infected persons are increasingly developing common health problems that also affect the general population and that require screening, management, and monitoring by primary care providers. Because people infected with HIV are typically seen by both an HIV specialist and a primary care provider, HIV specialists need to be familiar with primary care issues and primary care providers need to be familiar with HIV care recommendations in order to provide optimal care.

AFRICAN AMERICAN WOMEN BEAR A DISPROPORTIONATE BURDEN

In the United States, HIV was first reported in women in 1983 among those who had been steady sexual partners of males with acquired immune deficiency syndrome.¹ Although men with HIV still outnumber women, the number of women with HIV has increased rapidly. At the end of 2010 an estimated one in four people with HIV in the United States was female.²

African American women bear a disproportionate burden of the disease (Table 1).³ In 2010, women accounted for an estimated 9,500 (20%) of the approximately 45,000 new infections occurring in the United States. Of these newly infected women, 64% were black, 18% were white, and 15% were Hispanic. Yet blacks make up only about 12% of the US population, whites make up 68%, and Hispanics 14%.

Regardless of race or ethnicity, unprotected heterosexual contact is the most common mode of transmission of HIV in women.²

Although the overall rates of HIV infection in the United States are relatively low, certain areas of the country have rates similar to those in sub-Saharan Africa, where most HIV-infected people reside.⁴ The HIV Prevention Trials Network found that the incidence of HIV infection in US women living in these “hot spots,” with high rates of poverty and HIV, was 0.32% per year. Compare this with the 2009 estimate of HIV incidence in the general population of US black women of similar age (0.05% per year) and the adult incidence rates in Congo (0.28% per year) and Kenya (0.53% per year).⁵ To better understand the epidemiology of HIV infection in women and concentrate our prevention efforts, we need to focus on these hot spots.

Misinformation abounds in these hot spots, as does disease. In a survey of residents of the South Side Chicago Housing Authority facilities,⁶ many were aware that effective antiretroviral therapy existed, but one-fourth thought that there was an effective HIV vaccine, and 13% thought there was a cure.

In the early years, an HIV diagnosis was essentially a death sentence. Samji et al⁷ estimated that life expectancy of patients who were prescribed antiretroviral therapy in the United States and Canada increased from 36.1 years in 2000–2002 to 51.4 years in 2006–2007, with the greatest increases in those who started with a baseline CD4 count above 350 cells/mm³. Now, a 20-year-old HIV-positive person with a CD4 count greater than 350 cells/mm³ can expect to live into his or her early 70s.

But not all patients achieve these benefits. In 2009, despite major advances in diagnosis and treatment, HIV was the fourth leading cause of death among African American women ages 25 to 44, causing about 800 deaths, or 9% of all deaths in this group.⁸

TEST ALL, UNLESS THEY OPT OUT

Testing is vital in efforts to prevent and treat HIV infection. In 2006, the US Centers for Disease Control and Prevention (CDC) recommended that everyone between the ages of 13 and 64 be screened for HIV regardless of risk.⁹

The CDC recommends an opt-out strategy.⁹ Rather than ask a patient whether he or she wants to be tested for HIV, the provider says something like, “I advise all of my patients to have an HIV test; as long as you have no objection, we will send you to the lab to have it done.” This approach reduces barriers to HIV testing by eliminating pretest counseling and by making HIV testing routine and the standard of care. Separate consent is not required—clinicians just need to document whether the patient has accepted or declined the test.

Testing should be offered at least once and can be done in any health care setting, including primary care offices and clinics, emergency rooms, health departments, and urgent care centers.⁹ Patients at higher risk (injection drug users and their sex partners; people who exchange sex for money or drugs; sex partners of HIV-infected people; men who have sex with men; and heterosexuals who themselves or whose sex partners have had more than one sex partner since their most recent HIV test) should receive repeat screening annually.

HIV testing should also be offered to all pregnant women at entry into care and again in the third trimester. This strategy is cost-effective even in areas of low prevalence.⁹ Since 2006, other professional organizations have made HIV testing recommendations as well (Table 2).^9–12

A cost-effectiveness analysis suggested that routine opt-out testing is economically justified if the prevalence of HIV is greater than 0.2%.¹³

HIV-POSITIVE WOMEN NEED ROUTINE GYNECOLOGIC CARE

It is important for women with HIV to receive routine gynecologic care. Women with HIV have gynecologic problems similar to those of all women; however, they may be more vulnerable to certain conditions such as human papillomavirus (HPV) infection, which may be related to HIV disease or associated immunosuppression. In addition, pregnancy and family planning pose special challenges in this group.¹⁴

Cervical cancer screening

Effective screening and timely treatment of precancerous cervical lesions are key in preventing cervical cancer in women with or without HIV.

Persistent infection with HPV is necessary for the development of precancerous lesions as well as invasive cervical cancer. Most new cases of HPV infection in the general population resolve spontaneously within 2 years. However, in HIV-infected women, HPV infection is more likely to persist and progress to precancerous lesions of the cervix. This association is strongest in women with more compromised immune function as reflected by low CD4 cell counts and high viral loads.¹⁴ Women with HIV have higher rates of infection with high-risk HPV strains and of cervical intraepithelial neoplasia compared with their HIV-negative counterparts.¹⁴ The incidence of cervical cancer is five to six times higher in HIV-infected women in the United States than in the general population.¹⁵

According to guidelines from the Infectious Diseases Society of America,¹⁶ the American College of Obstetricians and Gynecologists,¹⁰ the CDC,¹⁷ and the American Cancer Society,¹⁸ all HIV-infected women should undergo cervical Papanicolaou (Pap) screening upon initiation into care, and this test should be repeated at 6 months and then annually if the results are normal. Patients with abnormalities on the Pap test should undergo colposcopy and, possibly, also biopsy. These abnormalities include atypical squamous cells of unknown significance and higher-grade lesions.¹⁶

Nearly one-fourth of HIV-positive women do not receive annual Pap smears despite engagement in care.¹⁹ This is unacceptable, because half of the cases of cervical cancer diagnosed in the United States are in women who never received appropriate screening, and an additional 10% are in women who have not been screened in the previous 5 years.¹⁹

In HIV-infected women who have had a total hysterectomy, whether to continue Pap testing depends on their history before the surgery. Continued vaginal Pap smear screening is recommended after hysterectomy (including removal of the cervix) in HIV-infected women who have a history of cervical intraepithelial neoplasia grades 2 or 3 or invasive cancer.^10,17,20

TREATING HIV IN WOMEN: SPECIAL CONSIDERATIONS

Because it is not yet possible to eradicate the HIV virus, the goals of antiretroviral therapy are to reduce HIV-associated morbidity and mortality, to restore and preserve immune function, to suppress viral load, and to prevent sexual and, in women, perinatal transmission of the virus.²¹

Antiretroviral therapy is recommended for all HIV-infected patients regardless of the CD4 count, although the strength of recommendation is weaker with higher CD4 counts (Table  3).²¹ The recommendations for starting antiretroviral therapy and the goals of treatment are the same for men and women. Table 4 summarizes the recommendations for adolescents and adults who are new to treatment.²¹ For women, additional factors that should be taken into account when considering a regimen include pregnancy potential and whether the drugs chosen for the regimen are considered safe in pregnancy.

Since the early years of the HIV epidemic, researchers have debated whether women attain the same benefits from antiretroviral therapy as men. US Food and Drug Administration investigators performed a meta-analysis of the efficacy outcomes in women in studies of antiretroviral drugs published between 2000 and 2008. They included randomized clinical trials reporting at least 48-week efficacy outcomes, with viral suppression defined as HIV RNA less than 50 copies/mL. The combined database included 40 trials of 16 drugs from 7 drug classes with a total of 20,328 HIV-positive participants. Overall, there were no clinically or statistically significant differences between the sexes in 48-week efficacy outcomes or in rates of trial discontinuation due to adverse events, loss to follow-up, or death.²²

Antiretroviral therapy may, however, cause different adverse effects in women than in men. For example:

Nevirapine, a nonnucleoside reverse transcriptase inhibitor, has been associated with the development of a rash and potentially life-threatening hepatotoxicity, more commonly in women than in men and at lower CD4 counts in women. This resulted in recommendations²¹ to avoid starting a nevirapine-containing regimen in women with CD4 counts greater than 250 cells/mm³ and in men with CD4 counts greater than 400 cells/mm³.

Ritonavir has been observed to cause a higher incidence of nausea and vomiting in women and a higher incidence of diarrhea in men. These are thought to be due to differences between men and women in weight and pharmacokinetics.²³

PRECONCEPTION COUNSELING FOR HIV-POSITIVE WOMEN

Preconception counseling is an essential component of both primary and preventive care and should be considered the standard of care for all women of reproductive age who have HIV.²⁴ Health care providers who fully understand the impact of HIV infection and associated comorbidities upon a woman’s reproductive health, fertility desires, and family planning needs are better prepared to assist in their patients’ reproductive health decisions.

The first few weeks of pregnancy are the most critical period in fetal development. During this time, a woman should be healthy and avoid any activities or substances that could cause adverse maternal or fetal outcomes. However, most patients present for prenatal care after this critical time period—thus the need for preconception counseling. Both the Infectious Diseases Society of America and the HIV Medicine Association recommend that all HIV-infected women of childbearing age be asked about their pregnancy plans and desires at the start of care and routinely thereafter.¹⁶

The goals of preconception care in women with HIV are to prevent unintended pregnancy, optimize maternal health before pregnancy, optimize pregnancy outcomes for mother and fetus, prevent perinatal HIV transmission, and prevent HIV transmission to an HIV-negative partner when trying to conceive.²⁴

Goal 1: Prevent unintended pregnancy

Nearly half of all pregnancies in the United States are unintended.²⁵ Moreover, the Women’s Interagency HIV Study²⁶ showed that women with HIV are underusing effective contraception. In the Medical Monitoring Project, 85% of the women who had been pregnant since being diagnosed with HIV said that at least one pregnancy was unplanned.²⁷

The consequences of unintended and unplanned pregnancies are serious and add significant burden to women, men, and families. Women who do not wish to become pregnant should be advised to use an effective method of contraception.

Contraception

Contraception use varies worldwide. Factors affecting its use include the methods available, patient choice, current health conditions, religious beliefs, perception of method effectiveness, and side effects.²⁴

The Women’s Interagency HIV Study evaluated trends in contraception use from 1998 to 2010. Condoms were the most common form of contraception, and their use changed little over time. Fewer than 15% of women with HIV used no contraception. The use of long-acting reversible contraception, including injectable progestins, implants, and intrauterine devices, which minimize the need for user adherence, increased among HIV-negative women but not among HIV-positive women.²⁸

The World Health Organization states that all available methods are safe for women with HIV except for spermicides with or without a diaphragm, as there is evidence linking the use of spermicides to an increased risk of HIV transmission (Table 5).²⁹

Some antiretroviral drugs may reduce the effectiveness of some contraceptives (Table 6); however, recommendations are based on pharmacokinetic studies, not on outcome studies. Condoms should be recommended not only to protect against pregnancy, but also to protect against sexually transmitted infections.

Goal 2: Optimize maternal health before pregnancy

Maternal health should be optimized before conceiving to reduce the risk of pregnancy-related morbidities and poor birth outcomes. This includes screening for other infections and ensuring that other comorbidities, such as hypertension, diabetes, substance abuse, and mental illness, are well managed with medications that are safe to use in pregnancy (Table 7).

Goal 3: Prevent perinatal HIV transmission

Educating the patient about perinatal transmission is a fundamental component of preconception counseling. Topics that need to be addressed are transmission risk and methods to reduce the risk, including not breastfeeding after delivery.

Goal 4: Prevent HIV transmission to an uninfected partner when trying to conceive

HIV-discordant couples who desire pregnancy should receive appropriate counseling about methods to minimize risk of transmission to the uninfected partner while trying to conceive. There are a number of effective methods and techniques, which are beyond the scope of this review. Key components of all methods are to screen for and treat sexually transmitted infections in both partners and to use effective antiretroviral therapy and attain maximal viral suppression in the HIV-positive partner.

Antiretroviral therapy for the HIV-infected partner significantly reduced the risk of HIV transmission by 96% in the HIV Prevention Trials Network 052 trial.³⁰ Of note: this reduction was the result of both risk-reduction counseling and antiretroviral therapy. This was the first randomized clinical trial to demonstrate that antiretroviral therapy in those with some preserved immune function (CD4 counts 350–500 cells/mm³) in conjunction with risk-reduction counseling can reduce HIV transmission to an uninfected partner.

Vaginal insemination without intercourse is another option for female-positive couples. The man ejaculates into a condom without spermicide, and the contents are introduced with a non-needle syringe or turkey baster. This can be done at home and confers no risk to the uninfected male partner.³¹ Chances of pregnancy can be maximized by insemination during the most fertile days of the menstrual cycle.

Preexposure prophylaxis combined with timed intercourse. In a study in Switzerland, the infected male partner was given antiretroviral therapy to suppress his viral load to less than 50 copies/mL for at least 6 months, and luteinizing hormone was measured every day in the urine of the noninfected female partner. When the urinary luteinizing hormone level reached a peak, the woman received a dose of tenofovir in the morning, the couple had unprotected intercourse, and the woman took a second dose the next morning. In 53 cases, none of the female partners seroconverted for HIV.³²

Health care providers need to document and update the relationship status, partner HIV status, and fertility desires of their HIV patients, both men and women, on a regular basis. Patient education should include awareness of referrals and options to help safely conceive when desired and achieve effective contraception when not.³³

WHEN HIV-POSITIVE WOMEN BECOME PREGNANT

Screening for HIV during pregnancy

The CDC recommends prenatal screening for HIV in the first trimester or at entry into prenatal care. A repeat HIV test should be offered in the third trimester for women at risk of acquiring HIV, for women who have signs or symptoms of early HIV infection, in health care settings where prenatal testing yields at least 1 case of HIV infection per 1,000 women screened, and in areas of high HIV incidence. If women present to labor and delivery with unknown HIV status, rapid HIV testing should be done.⁹

If a woman acquires HIV during pregnancy, the infection may not be detected and may be transmitted to the infant at birth. From 2002 to 2006 in New York State, 3,396 HIV-exposed babies were born. Of these, 9 (22%) of 41 infants born to mothers who acquired HIV during pregnancy became infected, compared with 1.8% of those born to mothers who acquired HIV before pregnancy. Maternal acquisition of HIV during pregnancy was documented in only 1.3% of perinatal HIV exposures, but it was associated with 9 (13.8%) of the 65 perinatal transmission cases.³⁴

Providers should be aware of the signs and symptoms of acute HIV infection and should have a low threshold for repeating HIV testing at any time during pregnancy. It has been estimated that 40% to 90% of patients with acute HIV infection experience fever, lymphadenopathy, pharyngitis, skin rash, myalgia, arthralgia, or other symptoms.³⁵ Providers often do not recognize acute HIV infection, however, because the symptoms are similar to those of other common illnesses. Also, some individuals with the condition have no symptoms.

Antiretroviral therapy during pregnancy

In a landmark study, AIDS Clinical Trial Group 076 demonstrated that zidovudine monotherapy given during pregnancy, labor, and delivery and to the newborn reduced the risk of HIV transmission to the infant by 67%, from 25% to 8%.³⁶ Other studies demonstrated that combination therapy further decreased the risk of HIV transmission to 1% to 2%.³⁷

The US Department of Health and Human Services recommends that all HIV-positive women who are pregnant receive effective combination antiretroviral therapy regardless of CD4 count to minimize the risk of mother-to-child transmission.³⁷

The goals of HIV treatment during pregnancy are to maintain the woman’s health, restore her immune system, suppress viral replication, and decrease the risk of perinatal transmission. The preferred antiretroviral therapy for pregnant women differs from that for nonpregnant women and is based on evolving experience and information about safety, efficacy, and tolerability in pregnancy (Table 8). A woman who presents for prenatal care on a suppressive regimen should continue that regimen as long as she can tolerate it because there is a risk of losing virologic control when switching regimens, and this may increase the risk of perinatal transmission.³⁷

Physiologic changes that occur during pregnancy may alter drug disposition, which could potentially lead to decreased drug exposure. Some of the changes include an increase in total body water, decreased protein binding, induction of hepatic metabolic pathways, and increased clearance of drugs eliminated by the kidneys.³⁸ These changes may be associated with incomplete virologic suppression, virologic failure, or development of drug resistance, so altered doses of some antiretroviral drugs or careful monitoring of viral load should be considered, particularly in the second and third trimester.

Delivery

Women who have a viral load greater than 1,000 copies/mL near the end of pregnancy should undergo a cesarean delivery at 38 weeks and, before surgery, should receive intravenous zidovudine to reduce the risk of perinatal transmission. For women with viral loads below the threshold of 1,000 copies/mL, there is no proven added benefit to cesarean delivery, and in this situation it should be performed only for standard obstetric indications. Antiretroviral regimens should be continued during labor.³⁷

HIV IN OLDER ADULTS

By 2015, approximately 50% of people with HIV will be over age 50.³⁹ Unfortunately, older people and their providers often underestimate their risk of acquiring HIV. Many older people are newly single and may engage in sexual activity with new partners. Also, older people may be reluctant to use condoms as the need for contraception is past.^40,41

Baseline HIV RNA levels tend to be higher and CD4 cell counts lower in patients diagnosed with HIV at older ages. These observations support previous ones that older HIV-infected patients may have advanced HIV disease at the time of diagnosis, perhaps in part due to delayed testing.⁴² Other possible factors are limited income, comorbid illness, polypharmacy, and insufficient data on drug interactions in the elderly.^41,42

A prompt diagnosis is important for older patients because HIV may accelerate aging, and aging may speed up HIV progression. Studies have shown that aging is associated with more rapid progression to AIDS, particularly among people who are older than 40 at seroconversion.⁴³ Other studies have reported that older patients have better virologic responses to antiretroviral therapy but have a blunted immune response, more AIDS-defining events, and a higher mortality rate than younger patients.⁴²

More than 30 years into the human immunodeficiency virus (HIV) epidemic, our understanding of the needs of women living with this virus continues to evolve. In the early years of the epidemic, managing HIV was all about preventing death and treating opportunistic infections. But now it is also about enabling patients to live long, healthy, and productive lives and preventing new HIV infections. In women, these goals can only be achieved by paying careful attention to sex-specific issues.

See related editorial

As a result of longer survival, HIV-infected persons are increasingly developing common health problems that also affect the general population and that require screening, management, and monitoring by primary care providers. Because people infected with HIV are typically seen by both an HIV specialist and a primary care provider, HIV specialists need to be familiar with primary care issues and primary care providers need to be familiar with HIV care recommendations in order to provide optimal care.

AFRICAN AMERICAN WOMEN BEAR A DISPROPORTIONATE BURDEN

In the United States, HIV was first reported in women in 1983 among those who had been steady sexual partners of males with acquired immune deficiency syndrome.¹ Although men with HIV still outnumber women, the number of women with HIV has increased rapidly. At the end of 2010 an estimated one in four people with HIV in the United States was female.²

African American women bear a disproportionate burden of the disease (Table 1).³ In 2010, women accounted for an estimated 9,500 (20%) of the approximately 45,000 new infections occurring in the United States. Of these newly infected women, 64% were black, 18% were white, and 15% were Hispanic. Yet blacks make up only about 12% of the US population, whites make up 68%, and Hispanics 14%.

Regardless of race or ethnicity, unprotected heterosexual contact is the most common mode of transmission of HIV in women.²

Although the overall rates of HIV infection in the United States are relatively low, certain areas of the country have rates similar to those in sub-Saharan Africa, where most HIV-infected people reside.⁴ The HIV Prevention Trials Network found that the incidence of HIV infection in US women living in these “hot spots,” with high rates of poverty and HIV, was 0.32% per year. Compare this with the 2009 estimate of HIV incidence in the general population of US black women of similar age (0.05% per year) and the adult incidence rates in Congo (0.28% per year) and Kenya (0.53% per year).⁵ To better understand the epidemiology of HIV infection in women and concentrate our prevention efforts, we need to focus on these hot spots.

Misinformation abounds in these hot spots, as does disease. In a survey of residents of the South Side Chicago Housing Authority facilities,⁶ many were aware that effective antiretroviral therapy existed, but one-fourth thought that there was an effective HIV vaccine, and 13% thought there was a cure.

In the early years, an HIV diagnosis was essentially a death sentence. Samji et al⁷ estimated that life expectancy of patients who were prescribed antiretroviral therapy in the United States and Canada increased from 36.1 years in 2000–2002 to 51.4 years in 2006–2007, with the greatest increases in those who started with a baseline CD4 count above 350 cells/mm³. Now, a 20-year-old HIV-positive person with a CD4 count greater than 350 cells/mm³ can expect to live into his or her early 70s.

But not all patients achieve these benefits. In 2009, despite major advances in diagnosis and treatment, HIV was the fourth leading cause of death among African American women ages 25 to 44, causing about 800 deaths, or 9% of all deaths in this group.⁸

TEST ALL, UNLESS THEY OPT OUT

Testing is vital in efforts to prevent and treat HIV infection. In 2006, the US Centers for Disease Control and Prevention (CDC) recommended that everyone between the ages of 13 and 64 be screened for HIV regardless of risk.⁹

The CDC recommends an opt-out strategy.⁹ Rather than ask a patient whether he or she wants to be tested for HIV, the provider says something like, “I advise all of my patients to have an HIV test; as long as you have no objection, we will send you to the lab to have it done.” This approach reduces barriers to HIV testing by eliminating pretest counseling and by making HIV testing routine and the standard of care. Separate consent is not required—clinicians just need to document whether the patient has accepted or declined the test.

Testing should be offered at least once and can be done in any health care setting, including primary care offices and clinics, emergency rooms, health departments, and urgent care centers.⁹ Patients at higher risk (injection drug users and their sex partners; people who exchange sex for money or drugs; sex partners of HIV-infected people; men who have sex with men; and heterosexuals who themselves or whose sex partners have had more than one sex partner since their most recent HIV test) should receive repeat screening annually.

HIV testing should also be offered to all pregnant women at entry into care and again in the third trimester. This strategy is cost-effective even in areas of low prevalence.⁹ Since 2006, other professional organizations have made HIV testing recommendations as well (Table 2).^9–12

A cost-effectiveness analysis suggested that routine opt-out testing is economically justified if the prevalence of HIV is greater than 0.2%.¹³

HIV-POSITIVE WOMEN NEED ROUTINE GYNECOLOGIC CARE

It is important for women with HIV to receive routine gynecologic care. Women with HIV have gynecologic problems similar to those of all women; however, they may be more vulnerable to certain conditions such as human papillomavirus (HPV) infection, which may be related to HIV disease or associated immunosuppression. In addition, pregnancy and family planning pose special challenges in this group.¹⁴

Cervical cancer screening

Effective screening and timely treatment of precancerous cervical lesions are key in preventing cervical cancer in women with or without HIV.

Persistent infection with HPV is necessary for the development of precancerous lesions as well as invasive cervical cancer. Most new cases of HPV infection in the general population resolve spontaneously within 2 years. However, in HIV-infected women, HPV infection is more likely to persist and progress to precancerous lesions of the cervix. This association is strongest in women with more compromised immune function as reflected by low CD4 cell counts and high viral loads.¹⁴ Women with HIV have higher rates of infection with high-risk HPV strains and of cervical intraepithelial neoplasia compared with their HIV-negative counterparts.¹⁴ The incidence of cervical cancer is five to six times higher in HIV-infected women in the United States than in the general population.¹⁵

According to guidelines from the Infectious Diseases Society of America,¹⁶ the American College of Obstetricians and Gynecologists,¹⁰ the CDC,¹⁷ and the American Cancer Society,¹⁸ all HIV-infected women should undergo cervical Papanicolaou (Pap) screening upon initiation into care, and this test should be repeated at 6 months and then annually if the results are normal. Patients with abnormalities on the Pap test should undergo colposcopy and, possibly, also biopsy. These abnormalities include atypical squamous cells of unknown significance and higher-grade lesions.¹⁶

Nearly one-fourth of HIV-positive women do not receive annual Pap smears despite engagement in care.¹⁹ This is unacceptable, because half of the cases of cervical cancer diagnosed in the United States are in women who never received appropriate screening, and an additional 10% are in women who have not been screened in the previous 5 years.¹⁹

In HIV-infected women who have had a total hysterectomy, whether to continue Pap testing depends on their history before the surgery. Continued vaginal Pap smear screening is recommended after hysterectomy (including removal of the cervix) in HIV-infected women who have a history of cervical intraepithelial neoplasia grades 2 or 3 or invasive cancer.^10,17,20

TREATING HIV IN WOMEN: SPECIAL CONSIDERATIONS

Because it is not yet possible to eradicate the HIV virus, the goals of antiretroviral therapy are to reduce HIV-associated morbidity and mortality, to restore and preserve immune function, to suppress viral load, and to prevent sexual and, in women, perinatal transmission of the virus.²¹

Antiretroviral therapy is recommended for all HIV-infected patients regardless of the CD4 count, although the strength of recommendation is weaker with higher CD4 counts (Table  3).²¹ The recommendations for starting antiretroviral therapy and the goals of treatment are the same for men and women. Table 4 summarizes the recommendations for adolescents and adults who are new to treatment.²¹ For women, additional factors that should be taken into account when considering a regimen include pregnancy potential and whether the drugs chosen for the regimen are considered safe in pregnancy.

Since the early years of the HIV epidemic, researchers have debated whether women attain the same benefits from antiretroviral therapy as men. US Food and Drug Administration investigators performed a meta-analysis of the efficacy outcomes in women in studies of antiretroviral drugs published between 2000 and 2008. They included randomized clinical trials reporting at least 48-week efficacy outcomes, with viral suppression defined as HIV RNA less than 50 copies/mL. The combined database included 40 trials of 16 drugs from 7 drug classes with a total of 20,328 HIV-positive participants. Overall, there were no clinically or statistically significant differences between the sexes in 48-week efficacy outcomes or in rates of trial discontinuation due to adverse events, loss to follow-up, or death.²²

Antiretroviral therapy may, however, cause different adverse effects in women than in men. For example:

Nevirapine, a nonnucleoside reverse transcriptase inhibitor, has been associated with the development of a rash and potentially life-threatening hepatotoxicity, more commonly in women than in men and at lower CD4 counts in women. This resulted in recommendations²¹ to avoid starting a nevirapine-containing regimen in women with CD4 counts greater than 250 cells/mm³ and in men with CD4 counts greater than 400 cells/mm³.

Ritonavir has been observed to cause a higher incidence of nausea and vomiting in women and a higher incidence of diarrhea in men. These are thought to be due to differences between men and women in weight and pharmacokinetics.²³

PRECONCEPTION COUNSELING FOR HIV-POSITIVE WOMEN

Preconception counseling is an essential component of both primary and preventive care and should be considered the standard of care for all women of reproductive age who have HIV.²⁴ Health care providers who fully understand the impact of HIV infection and associated comorbidities upon a woman’s reproductive health, fertility desires, and family planning needs are better prepared to assist in their patients’ reproductive health decisions.

The first few weeks of pregnancy are the most critical period in fetal development. During this time, a woman should be healthy and avoid any activities or substances that could cause adverse maternal or fetal outcomes. However, most patients present for prenatal care after this critical time period—thus the need for preconception counseling. Both the Infectious Diseases Society of America and the HIV Medicine Association recommend that all HIV-infected women of childbearing age be asked about their pregnancy plans and desires at the start of care and routinely thereafter.¹⁶

The goals of preconception care in women with HIV are to prevent unintended pregnancy, optimize maternal health before pregnancy, optimize pregnancy outcomes for mother and fetus, prevent perinatal HIV transmission, and prevent HIV transmission to an HIV-negative partner when trying to conceive.²⁴

Goal 1: Prevent unintended pregnancy

Nearly half of all pregnancies in the United States are unintended.²⁵ Moreover, the Women’s Interagency HIV Study²⁶ showed that women with HIV are underusing effective contraception. In the Medical Monitoring Project, 85% of the women who had been pregnant since being diagnosed with HIV said that at least one pregnancy was unplanned.²⁷

The consequences of unintended and unplanned pregnancies are serious and add significant burden to women, men, and families. Women who do not wish to become pregnant should be advised to use an effective method of contraception.

Contraception

Contraception use varies worldwide. Factors affecting its use include the methods available, patient choice, current health conditions, religious beliefs, perception of method effectiveness, and side effects.²⁴

The Women’s Interagency HIV Study evaluated trends in contraception use from 1998 to 2010. Condoms were the most common form of contraception, and their use changed little over time. Fewer than 15% of women with HIV used no contraception. The use of long-acting reversible contraception, including injectable progestins, implants, and intrauterine devices, which minimize the need for user adherence, increased among HIV-negative women but not among HIV-positive women.²⁸

The World Health Organization states that all available methods are safe for women with HIV except for spermicides with or without a diaphragm, as there is evidence linking the use of spermicides to an increased risk of HIV transmission (Table 5).²⁹

Some antiretroviral drugs may reduce the effectiveness of some contraceptives (Table 6); however, recommendations are based on pharmacokinetic studies, not on outcome studies. Condoms should be recommended not only to protect against pregnancy, but also to protect against sexually transmitted infections.

Goal 2: Optimize maternal health before pregnancy

Maternal health should be optimized before conceiving to reduce the risk of pregnancy-related morbidities and poor birth outcomes. This includes screening for other infections and ensuring that other comorbidities, such as hypertension, diabetes, substance abuse, and mental illness, are well managed with medications that are safe to use in pregnancy (Table 7).

Goal 3: Prevent perinatal HIV transmission

Educating the patient about perinatal transmission is a fundamental component of preconception counseling. Topics that need to be addressed are transmission risk and methods to reduce the risk, including not breastfeeding after delivery.

Goal 4: Prevent HIV transmission to an uninfected partner when trying to conceive

HIV-discordant couples who desire pregnancy should receive appropriate counseling about methods to minimize risk of transmission to the uninfected partner while trying to conceive. There are a number of effective methods and techniques, which are beyond the scope of this review. Key components of all methods are to screen for and treat sexually transmitted infections in both partners and to use effective antiretroviral therapy and attain maximal viral suppression in the HIV-positive partner.

Antiretroviral therapy for the HIV-infected partner significantly reduced the risk of HIV transmission by 96% in the HIV Prevention Trials Network 052 trial.³⁰ Of note: this reduction was the result of both risk-reduction counseling and antiretroviral therapy. This was the first randomized clinical trial to demonstrate that antiretroviral therapy in those with some preserved immune function (CD4 counts 350–500 cells/mm³) in conjunction with risk-reduction counseling can reduce HIV transmission to an uninfected partner.

Vaginal insemination without intercourse is another option for female-positive couples. The man ejaculates into a condom without spermicide, and the contents are introduced with a non-needle syringe or turkey baster. This can be done at home and confers no risk to the uninfected male partner.³¹ Chances of pregnancy can be maximized by insemination during the most fertile days of the menstrual cycle.

Preexposure prophylaxis combined with timed intercourse. In a study in Switzerland, the infected male partner was given antiretroviral therapy to suppress his viral load to less than 50 copies/mL for at least 6 months, and luteinizing hormone was measured every day in the urine of the noninfected female partner. When the urinary luteinizing hormone level reached a peak, the woman received a dose of tenofovir in the morning, the couple had unprotected intercourse, and the woman took a second dose the next morning. In 53 cases, none of the female partners seroconverted for HIV.³²

Health care providers need to document and update the relationship status, partner HIV status, and fertility desires of their HIV patients, both men and women, on a regular basis. Patient education should include awareness of referrals and options to help safely conceive when desired and achieve effective contraception when not.³³

WHEN HIV-POSITIVE WOMEN BECOME PREGNANT

Screening for HIV during pregnancy

The CDC recommends prenatal screening for HIV in the first trimester or at entry into prenatal care. A repeat HIV test should be offered in the third trimester for women at risk of acquiring HIV, for women who have signs or symptoms of early HIV infection, in health care settings where prenatal testing yields at least 1 case of HIV infection per 1,000 women screened, and in areas of high HIV incidence. If women present to labor and delivery with unknown HIV status, rapid HIV testing should be done.⁹

If a woman acquires HIV during pregnancy, the infection may not be detected and may be transmitted to the infant at birth. From 2002 to 2006 in New York State, 3,396 HIV-exposed babies were born. Of these, 9 (22%) of 41 infants born to mothers who acquired HIV during pregnancy became infected, compared with 1.8% of those born to mothers who acquired HIV before pregnancy. Maternal acquisition of HIV during pregnancy was documented in only 1.3% of perinatal HIV exposures, but it was associated with 9 (13.8%) of the 65 perinatal transmission cases.³⁴

Providers should be aware of the signs and symptoms of acute HIV infection and should have a low threshold for repeating HIV testing at any time during pregnancy. It has been estimated that 40% to 90% of patients with acute HIV infection experience fever, lymphadenopathy, pharyngitis, skin rash, myalgia, arthralgia, or other symptoms.³⁵ Providers often do not recognize acute HIV infection, however, because the symptoms are similar to those of other common illnesses. Also, some individuals with the condition have no symptoms.

Antiretroviral therapy during pregnancy

In a landmark study, AIDS Clinical Trial Group 076 demonstrated that zidovudine monotherapy given during pregnancy, labor, and delivery and to the newborn reduced the risk of HIV transmission to the infant by 67%, from 25% to 8%.³⁶ Other studies demonstrated that combination therapy further decreased the risk of HIV transmission to 1% to 2%.³⁷

The US Department of Health and Human Services recommends that all HIV-positive women who are pregnant receive effective combination antiretroviral therapy regardless of CD4 count to minimize the risk of mother-to-child transmission.³⁷

The goals of HIV treatment during pregnancy are to maintain the woman’s health, restore her immune system, suppress viral replication, and decrease the risk of perinatal transmission. The preferred antiretroviral therapy for pregnant women differs from that for nonpregnant women and is based on evolving experience and information about safety, efficacy, and tolerability in pregnancy (Table 8). A woman who presents for prenatal care on a suppressive regimen should continue that regimen as long as she can tolerate it because there is a risk of losing virologic control when switching regimens, and this may increase the risk of perinatal transmission.³⁷

Physiologic changes that occur during pregnancy may alter drug disposition, which could potentially lead to decreased drug exposure. Some of the changes include an increase in total body water, decreased protein binding, induction of hepatic metabolic pathways, and increased clearance of drugs eliminated by the kidneys.³⁸ These changes may be associated with incomplete virologic suppression, virologic failure, or development of drug resistance, so altered doses of some antiretroviral drugs or careful monitoring of viral load should be considered, particularly in the second and third trimester.

Delivery

Women who have a viral load greater than 1,000 copies/mL near the end of pregnancy should undergo a cesarean delivery at 38 weeks and, before surgery, should receive intravenous zidovudine to reduce the risk of perinatal transmission. For women with viral loads below the threshold of 1,000 copies/mL, there is no proven added benefit to cesarean delivery, and in this situation it should be performed only for standard obstetric indications. Antiretroviral regimens should be continued during labor.³⁷

HIV IN OLDER ADULTS

By 2015, approximately 50% of people with HIV will be over age 50.³⁹ Unfortunately, older people and their providers often underestimate their risk of acquiring HIV. Many older people are newly single and may engage in sexual activity with new partners. Also, older people may be reluctant to use condoms as the need for contraception is past.^40,41

Baseline HIV RNA levels tend to be higher and CD4 cell counts lower in patients diagnosed with HIV at older ages. These observations support previous ones that older HIV-infected patients may have advanced HIV disease at the time of diagnosis, perhaps in part due to delayed testing.⁴² Other possible factors are limited income, comorbid illness, polypharmacy, and insufficient data on drug interactions in the elderly.^41,42

A prompt diagnosis is important for older patients because HIV may accelerate aging, and aging may speed up HIV progression. Studies have shown that aging is associated with more rapid progression to AIDS, particularly among people who are older than 40 at seroconversion.⁴³ Other studies have reported that older patients have better virologic responses to antiretroviral therapy but have a blunted immune response, more AIDS-defining events, and a higher mortality rate than younger patients.⁴²

In this issue of the Cleveland Clinic Journal of Medicine, Drs. Short and Anderson give an overview of the epidemic of human immunodeficiency virus (HIV) infection in US women and the various aspects of health care of this group, including pregnancy.¹ They introduce a much broader topic and bring to light a number of additional concerns.

HIV PREYS ON THE VULNERABLE

The authors review epidemiologic trends and the evolving demographics of HIV, which deserve specific discussion.

See related article

In the early years of the epidemic, ie, the early 1980s, HIV infection in women was overshadowed by the epidemic in men, particularly men who have sex with men. The epidemic in men who have sex with men remains the larger component of the HIV picture in the United States. But worldwide, HIV is an evenly balanced problem, with nearly half of all infections occurring in women.² Women have received much more attention recently.

In the United States, about 300,000 women are living with HIV, and 10% of them are unaware of it. Between 1985 and 2013, the number of HIV cases in US women tripled.

The epidemic continues to disproportionately affect women of color. Two-thirds of all women with HIV are African American,² and estimates suggest that 1 of every 32 African American women will acquire HIV during her lifetime. On a positive note, there was a 20% reduction in new infections among African American women between 2008 and 2010.³

The epidemic preys on the vulnerable and is fueled by poverty, lack of education (general and health literacy), substance abuse, and restricted access to health care. Major metropolitan areas such as New York, Washington, DC, Miami, and Los Angeles are “hot spots,” where high concentrations of infected people reside.⁴

Many women underestimate or do not perceive their susceptibility. They unknowingly acquire HIV infection from their male partners, many of whom are unaware of their infection. Some of their partners may lead a dual life of bisexuality. In some areas, an estimated 20% of men who have sex with men also engage in sex with women.⁵ If these women contract the disease, they may be diagnosed at a late stage and when they are symptomatic, or coincidentally during pregnancy and childbirth.

Negotiating safe sex practices can be difficult for a woman. She may perceive or lack empowerment to do so, fearing rejection, isolation, or violence. Sexual violence may have been initiated in childhood, through intimate partners, rape, sex trafficking, or prostitution. Patterns vary throughout the world, but sexual violence is more common than perceived.⁶ Because of shame, embarrassment, and isolation, many victims do not seek medical care and so may carry undiagnosed infections. Even when they access care, they are less likely to remain in the HIV care system.⁷ Greater efforts are needed to reach these women, make them feel supported in care, and keep them in the system.

TESTING IS CRUCIAL

Diagnosis remains a weak link in the chain of care for both men and women. Success has been noted in the form of a marked reduction in cases of mother-to-child transmission, thanks to near-universal opt-out screening during pregnancy or at delivery.

If appropriate routine testing were done for all people, as advocated by the US Centers for Disease Control and Prevention guidelines,⁸ more cases could be diagnosed, behaviors changed, and treatment offered. Control of HIV through treatment can lead to a 96% reduction in transmission between serodiscordant partners, as demonstrated in HPTN 052, an ongoing phase 3 trial.⁹ Early diagnosis and treatment offer the potential for improved immune regeneration and healthier lives.

PRE-EXPOSURE PROPHYLAXIS

Pre-exposure prophylaxis (PrEP) is one approach to empowering women and preventing HIV infection. Studies have demonstrated the efficacy of this approach, although some studies have not.^10,11

An important finding in the failed studies appeared to be a lack of adherence to the regimen.¹¹ Unless taken faithfully, PrEP will not succeed. Additionally, there may be inherent differences in outcomes for unknown reasons. Lack of access to the necessary two-drug combination regimen is another barrier.

PrEP is expensive, requires regular monitoring, and requires patients to remain engaged in medical care. Currently, not all medical programs offer PrEP, and not all insurance policies cover it. Further insight into long-term side effects and complications is needed.

Although PrEP is an attractive concept and a reality for some, it is an incomplete solution to prevention at this time.

MEN AND WOMEN ARE DIFFERENT

Men and women are different physiologically and psychologically. Women typically have a lower body mass, lower bone mass, and higher content of body fat. As a result, women may differ from men in their ability to tolerate medications, and long-term side effects may be more pronounced.

Women are also more likely to place family responsibilities above self-preservation and personal health concerns. As a result, providing for and taking care of their children takes precedence over care of their own health.

Providing care to women presents many challenges and opportunities to improve their health. Health care access, transportation, assistance with child care during medical visits, the availability of counseling to deal with shame, guilt, and depression, and maintaining women within the care system are but a few examples.

AGING WITH HIV: STUDY NEEDED

Antiretroviral therapy has enabled patients to survive and often to reach a normal life expectancy if the infection is diagnosed and treated early. As a result, HIV-associated causes of death have been replaced by non-HIV comorbidities typical of aging, such as cardiovascular disease, organ failure (heart, lung, kidney, liver), non-HIV cancers, and bone disease.

Women face unique aspects of aging with menopause, including an accelerated rate of bone loss resulting in osteoporosis. HIV itself and some antiretroviral drugs may increase the loss of bone mineral density. Alcohol abuse, sedentary lifestyle, smoking, hepatitis C co-infection, and poor nutrition also contribute to this problem. Bone disease and many other aspects of aging and HIV in women require more research and intervention.

Other areas that need to be studied are the unique mucosal immune system of the female genital tract, the interplay of sex hormones and the immune system, the role of genital tract inflammation in increasing the risk of HIV acquisition, sexual violence and HIV acquisition, and the safety and efficacy of PrEP for women. This will require prioritization and ongoing funding, which is becoming scarcer. If there is to be hope of containing this disease, our efforts to understand it must not diminish.